3-arylamino pyridine derivatives

ABSTRACT

The invention provides novel, substituted 3-arylamino pyridine compounds (I) pharmaceutically acceptable salts, solvates and prodrug compounds thereof, wherein W, R1, R2, R9, R10, R11, R12, R13, R14 are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer, restenosis and inflammation. Also disclosed is the use of such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing such compounds.

RELATED APPLICATIONS

This application is the U.S. National Stage of International ApplicationNo. PCT/EP2005/011257, filed Oct. 19, 2005, published in English, andclaims priority under 35 U.S.C. §119 or §365 to European Application No.04024967.4, filed Oct. 20, 2004.

FIELD OF THE INVENTION

The invention relates to a series of substituted 3-arylamino pyridinederivatives that are useful in the treatment of hyperproliferativediseases, such as cancer and inflammation, in mammals. Also disclosed isthe use of such compounds in the treatment of hyperproliferativediseases in mammals, especially humans, and pharmaceutical compositionscontaining such compounds.

SUMMARY OF THE RELATED ART

The Ras/Raf/MEK/ERK pathway is a central signal transduction pathway,which transmits signals from multiple cell surface receptors totranscription factors in the nucleus which regulate gene expression.This pathway is frequently referred to as the MAP kinase pathway as MAPKstands for mitogen-activated protein kinase indicating that this pathwaycan be stimulated by mitogens, cytokines and growth factors (Steelman etal., Leukemia 2004, 18, 189-218). Depending upon the stimulus and celltype, this pathway can transmit signals, which result in the preventionor induction of apoptosis or cell cycle progression. The Ras/Raf/MEK/ERKpathway has been shown to play important roles in cell proliferation andthe prevention of apoptosis. Aberrant activation of this pathway iscommonly observed in malignantly transformed cells. Amplification of rasproto-oncogenes and activating mutations that lead to the expression ofconstitutively active Ras proteins are observed in approximately 30% ofall human cancers (Stirewalt et al., Blood 2001, 97, 3589-95). Mutated,oncogenic forms of Ras are found in 50% of colon and >90% pancreaticcancers as well as many other types of cancers (Kohl et al., Science1993, 260, 1934-1937). The effects of Ras on proliferation andtumorigenesis have been documented in immortal cell lines (McCubrey etal., Int J Oncol 1995, 7,295-310). bRaf mutations have been identifiedin more than 60%. of malignant melanoma (Davies. H et al., Nature 2002,417, 949-954). Given the high level of mutations that have been detectedat Ras, this pathway has always been considered a key target fortherapeutic intervention (Chang et al., Leukemia 2003, 77,1263-93),

The Ras/Raf/MEK/ERK signaling pathway can exert proliferative orantiproliferative effects through downstream transcription factortargets including NF-κB, CREB, Ets-1, AP-1 and c-Myc. ERKs can directlyphosphorylate Ets-1, AP-1 and c-Myc, which lead to their activation.Alternatively, ERKs can phosphorylate and activate a downstream kinasetarget RSK, which then phosphorylates and activates transcriptionfactors, such as CREB. These transcription factors induce the expressionof genes important for cell cycle progression, for example, Cdks,cyclins, growth factors, and apoptosis prevention, for example,antiapoptotic Bcl-2 and cytokines. Overall, treatment of cells withgrowth factors leads to the activation of ERKs which results inproliferation and, in some cases, differentiation (Lewis et al., Adv.Cancer Res, 1998, 74, 49-139).

MEK proteins are the primary downstream targets of Raf. The MEK familyof genes consists of five genes: MEK1, MEK2, MEK3, MEK4 and MEK5. Thisfamily of dual-specificity kinases has both serine/threonine andtyrosine kinase activity. The structure of MEK consists of anamino-terminal negative regulatory domain and a carboxy-terminal MAPkinase-binding domain, which is necessary for binding and activation ofERKs. Deletion of the regulatory MEK1 domain results in constitutiveMEK1 and ERK activation (Steelman et al., Leukemia 2004, 18, 189-218).

MEK1 is a 393-amino-acid protein with a molecular weight of 44 kDa(Crews et al., Science 1992, 258, 478-80). MEK1 is modestly expressed inembryonic development and is elevated in adult tissue with the highestlevels detected in brain tissue. MEK1 requires phosphorylation of S218and S222 for activation, and substitution of these residues with D orglutamic acid (E) led to an increase in activity and foci formation inNIH3T3 cells (Huang et al., Mol Biol Cell, 1995, 6, 237-45).Constitutive activity of MEK1 in primary cell culture promotessenescence and induces p53 and p16^(INK4a), and the opposite wasobserved in immortalized cells or cells lacking either p53 orp16^(INK4a) (Lin et al., Genes Dev, 1998, 12, 3008-3019). Constitutiveactivity of MEK1 inhibits NF-κB transcription by negatively regulatingp38^(MAPK) activity (Carter et al., J Biol C hem 2000, 275, 27858-64).The main physiological substrates of MEK are the members of the ERK(extracellular signal-regulated kinase) or MAPK (mitogen activatedprotein kinase) family of genes. Aberrant expression of MEK1 has beendetected in many different types of cancer, and mutated forms of MEK1will transform fibroblast, hematopoietic and other cell types.

Constitutive activation of MEK1 results in cellular transformation. Ittherefore represents a likely target for pharmacological intervention inproliferative and inflammatory diseases (Lee et al., Nature 1994, 372,739-746; Dudley et al., Proc. Natl. Acad. Sci. U.S.A. 1995, 92,7686-7689).

Useful inhibitors of MEK have been developed that show potentialtherapeutic benefit in several studies. For example, small molecule MEKinhibitors have been shown to inhibit human tumor growth in nude mousexenografts (Yeh, T. et al, Proceedings of the American Association ofCancer Research 2004, 45, Abs 3889 and Lee, P. et al., Proceedings ofthe American Association of Cancer Research 2004, 45, Abs 3890). MEKinhibitors also entered clinical trials, i.e. ARRY142886 (Wallace, E. etal, Proceedings of the American Association of Cancer Research 2004, 45,Abs 3891), PD-0325901 (Swanton C, Johnston S IDDB MEETING REPORT 2003,February 13-1) and PD-184352 (Waterhouse et al., Proceedings of theAmerican Society for Clinical Oncology 2003, 22, Abs 816).

Compounds suitable as MEK inhibitors are also disclosed in U.S. Pat. No.5,525,625; WO 98/43960; WO 99/01421; WO 99/01426; WO 00/41505; WO00/42002; WO 00/42003; WO 00/41994; WO 00/42022; WO 00/42029; WO00/68201; WO 01/68619; WO 02/06213; WO 03/077855; WO03/077914;WO2004/005284; WO2004/056789.

However, PD-184352 was lacking efficacy in clinical phase II trials.Tumors were much less responsive, as no partial responses and only a fewpatients with stable disease were observed. As a result, the clinicaltrials of this molecule were suspended (McInnes C IDDB MEETING REPORT2003). PD-184352 was limited by poor solubility, high metabolicclearance and low bioavailability. This exemplifies the need for novelMEK inhibitors with superior pharmacological properties.

DESCRIPTION OF THE INVENTION

In view of the foregoing it is the object of the present invention toprovide novel MEK inhibitors useful in the treatment ofhyperproliferative diseases related to the hyperactivity of MEK as wellas diseases modulated by the MEK cascade, such as cancer andinflammation, in mammals with superior pharmacological properties bothwith respect to their activities as well as their solubility, metabolicclearance and bioavailability characteristics.

As a result, this invention provides novel, substituted 3-arylaminopyridine derivatives and pharmaceutically acceptable salts, solvates orprodrugs thereof, that are MEK inhibitors and useful in the treatment ofthe above mentioned diseases.

The compounds are defined by Formula (I):

a pharmaceutically acceptable salt, solvate or prodrug thereof,wherein:

-   R₁, R₂, R₉, R₁₀, R₁₁ R₁₂, R₁₃ and R₁₄ are independently selected    from hydrogen, halogen, cyano, nitro, azido, —OR₃, —C(O)R₃,    —C(O)OR₃, —NR₄C(O)OR₆, —OC(O)R₃, —NR₄S(O)_(j)R₆, —S(O)_(j)NR₃R₄,    —S(O)_(j)NR₄C(O)R₃, —C(O)NR₄S(O)_(j)R₆, S(O)_(j)R₆, —NR₄C(O)R₃,    —C(O)NR₃R₄, —NR₅C(O)NR₃R₄, —NR₅C(NCN)NR₃R₄, —NR₃R₄ and C₁-C₁₀ alkyl,    C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀    cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR₄R₅)_(m)-aryl,    aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,    heterocyclylalkyl, —O(CR₄R₅)_(m)-aryl, —NR₄(CR₄R₅)_(m)-aryl,    —O(CR₄R₅)_(m)-heteroaryl, —NR₄(CR₄R₅)_(m), heteroaryl,    —O(CR₄R₅)_(m)-heterocyclyl, —NR₄(CR₄R₅)_(m)-heterocyclyl, and    —S(C₁-C₂ alkyl) substituted with 1 to 5 F, where each alkyl,    alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are    substituted or unsubstituted;-   R₃ is selected from hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂₋₁₀    alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,    aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and    heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl,    aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;-   R₄ is selected from hydrogen or C₁-C₆ alkyl whereby alkyl may be    substituted or unsubstituted; or-   R₃ and R₄ can be taken together with the atom to which they are    attached to form a 4 to 10 membered heteroaryl or heterocyclic ring,    each of which is substituted or unsubstituted;-   R₅ is selected from hydrogen or C₁-C₆ alkyl whereby alkyl may be    substituted or unsubstituted; or-   R₄ and R₅ can be taken together with the atom to which they are    attached to form a 4 to 10 membered carbocyclic, heteroaryl or    heterocyclic ring, each of which is substituted or unsubstituted;-   R₆ is selected from trifluoromethyl; and C₁-C₁₀ alkyl, C₃-C₁₀    cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl,    aryl, heteroaryl and heterocyclyl substituted or unsubstituted;-   W is selected from heteroaryl containing 1-4 heteroatoms or    heterocyclyl containing 1-4 heteroatoms each of which is    unsubstituted or substituted by 1 to 5 substituents ZR₁₅; or W is    —C(O)OR₁₅, —C(O)NR₄R₁₅, —C(O)NR₄OR₁₅, —C(O)(C₃-C₁₀ cycloalkyl),    —C(O)(C₂-C₁₀ alkyl), —C(O)(aryl), —C(O)(heteroaryl),    —C(O)(heterocyclyl), S(O)_(j)NR₄R₁₅, S(O)_(j)NR₄OR₁₅,    —S(O)_(j)NR₄C(O)R₁₅, —C(O)NR₄S(O)_(j)R₆, —C(O)NR₄NR₄R₁₅,    —C(O)C(O)R₁₅, —C(O)CR′R″C(O)R₁₅, —NR′R″, —NR′C(O)R′, —NR′S(O)_(j)R′,    —NRC(O)NR′R″, NR′S(O)_(j)NR′R″, or —C(O)NR₄NR₄C(O)R₁₅;-   Z is a bond, NR₁₆, O, NR₁₆SO₂ or S;-   R₁₅ is independently selected from hydrogen, trifluoromethyl, C₁-C₁₀    alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀    cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl,    alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is    substituted or unsubstituted;-   R₁₆ is selected from hydrogen or C₁-C₁₀ alkyl, or R₁₅ and R₁₆ form    together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and    optionally an O atom, said ring being substituted or unsubstituted;-   X is N or N→O;-   m is 0, 1, 2, 3, 4 or 5; and-   j is 1 or 2.

Preferred are compounds of Formula (II),

a pharmaceutically acceptable salt, solvate or prodrug thereof,wherein:

-   R₁, R₂, R₉, R₁₀, R₁₁ R₁₂, R₁₃ and R₁₄ are independently selected    from hydrogen, halogen, cyano, nitro, azido, —OR₃, —NR₄C(O)OR₆,    —OC(O)R₃, —NR₄S(O)_(j)R₆, —S(O)_(j)NR₃R₄, —S(O)_(j)NR₄C(O)R₃,    —C(O)NR₄S(O)_(j)R₆, S(O)_(j)R₆, —NR₄C(O)R₃, —C(O)NR₃R₄,    —NR₅C(O)NR₃R₄, —NR₅C(NCN)NR₃R₄, —NR₃R₄ and C₁-C₁₀ alkyl, C₂-C₁₀    alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,    —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR₄R₅)_(m)-aryl, aryl, arylalkyl,    heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,    —O(CR₄R₅)_(m)-aryl, —NR₄(CR₄R₅)_(m)-aryl, —O(CR₄R₅)_(m)-heteroaryl,    —NR₄(CR₄R₅)_(m), heteroaryl, —O(CR₄R₅)_(m)-heterocyclyl,    —NR₄(CR₄R₅)_(m)-heterocyclyl, and —S(C₁-C₂ alkyl) substituted with 1    to 5 F, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,    heteroaryl and heterocyclyl are substituted or unsubstituted;-   R₃ is selected from hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂₋₁₀    alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,    arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and    heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl,    heteroaryl and heterocyclyl is substituted or unsubstituted; or aryl    which is unsubstituted or substituted with 1 to 5 groups    independently selected from oxo, halogen, nitro, CF₃, CHF₂, CH₂F,    OCF₃, OCHF₂, OCH₂F, azido, N′SO₂R″″, SO₂NR″, C(O)R′, C(O)OR′,    OC(O)R′, NR′C(O)OR″″, NR′C(O)R″, C(O)NR′R″, SR″″, S(O)R″″, SO₂R′,    NR′R″, NR″C(O)NR″R′″, NR′C(NCN)NR″R′″, OR′, aryl, heteroaryl,    arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;-   R₄ is selected from hydrogen or C₁-C₆ alkyl whereby alkyl may be    substituted or unsubstituted; or-   R₃ and R₄ can be taken together with the atom to which they are    attached to form a 4 to 10 membered heteroaryl or heterocyclic ring,    each of which is substituted or unsubstituted;-   R₅ is selected from hydrogen or C₁-C₆ alkyl whereby alkyl may be    substituted or unsubstituted; or-   R₄ and R₅ can be taken together with the atom to which they are    attached to form a 4 to 10 membered carbocyclic, heteroaryl or    heterocyclic ring, each of which is substituted or unsubstituted;-   R₆ is selected from trifluoromethyl; and C₁-C₁₀ alkyl, C₃-C₁₀    cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl,    aryl, heteroaryl and heterocyclyl substituted or unsubstituted;-   R′, R″ and R′″ are independently selected from hydrogen, C₁-C₄    alkyl, C₂-C₄ alkenyl, aryl and arylalkyl;-   R″″ is selected from C₁-C₄ alkyl, C₁-C₄ alkenyl, aryl and arylalkyl;-   W is selected from heteroaryl containing 1-4 heteroatoms or    heterocyclyl containing 1-4 heteroatoms each of which is    unsubstituted or substituted by 1 to 5 substituents ZR₁₅; or W is    —C(O)OR₁₅, —C(O)NR₄R₁₅, —C(O)NR₄OR₁₅, —C(O)(C₃-C₁₀ cycloalkyl),    —C(O)(heterocyclyl), S(O)_(j)NR₄R₁₅, S(O)_(j)NR₄OR₁₅,    —S(O)_(j)NR₄C(O)R₁₅, —C(O)NR₄S(O)_(j)R₆, —C(O)NR₄NR₄R₁₅,    —C(O)C(O)R₁₅, —C(O)CR′R″C(O)R₁₅, —NR′R″, —NR′C(O)R′, —NR′S(O)_(j)R′,    —NRC(O)NR′R″, NR′S(O)_(j)NR′R″, or —C(O)NR₄NR₄C(O)R₁₅;-   and when W is C(O)OH, then R₁, R₂, R₁₂, R₁₃ and R₁₄ are    independently selected from hydrogen, halogen, cyano, nitro, azido,    —NR₄C(O)OR₆, —OC(O)R₃, —S—C₁-C₂ alkyl substituted with 1 to 5 F,    —NR₄S(O)_(j)R₆, —S(O)_(j)NR₃R₄, —S(O)_(j)NR₄C(O)R₃,    —C(O)NR₄S(O)_(j)R₆, S(O)_(j)R₆, —NR₄C(O)R₃, —NR₅C(O)NR₃R₄,    —NR₅C(NCN)NR₃R₄ and C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,    C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),    —S(O)_(j)(CR₄R₅)_(m)-aryl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, heterocyclyl, heterocyclylalkyl,    —O(CR₄R₅)_(m)-aryl, —NR₄(CR₄R₅)_(m)-aryl, —O(CR₄R₅)_(m)-heteroaryl,    —NR₄(CR₄R₅)_(m), heteroaryl, —O(CR₄R₅)_(m)-heterocyclyl and    —NR₄(CR₄R₅)_(m)-heterocyclyl, where each alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or    unsubstituted; —NR₃₃R₄₄, C(O)NR₃R₄₄, or OR₃₃, whereby R₃₃ is    selected from hydrogen, CF₃, CHF₂, CH₂F, C₂-C₁₀ alkyl, C₂₋₁₀    alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,    arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and    heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl,    heteroaryl and heterocyclyl is substituted or unsubstituted, and R₄₄    is selected from hydrogen, CF₃, CHF₂, CH₂F and C₂-C₆ alkyl;-   Z is a bond, NR₁₆, O, NR₁₆SO₂ or S.-   R₁₅ is independently selected from hydrogen, trifluoromethyl, C₁-C₁₀    alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀    cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl,    alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is    substituted or unsubstituted;-   R₁₆ is selected from hydrogen or C₁-C₁₀ alkyl, or R₁₅ and R₁₆ form    together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and    optionally an O atom, said ring being substituted or unsubstituted;-   X is N or N→O;-   m is 0, 1, 2, 3, 4 or 5; and-   j is 1 or 2

In one embodiment the compounds as defined by Formula (II) do notinclude the following compounds:

3-(4-Methoxy-phenylamino)-isonicotinic acid, that has been described asan intermediate in the synthesis of benzonaphthyridine derivatives asanti-malarial agents,

3-Phenylamino-isonicotinic acid methyl ester, that has been described asan anti-allergic agent (Sherlock et al., J. Med. Chem. 1988, 31,2108-21);

2,3,6-Trifluoro-5-phenylamino-isonicotinic acid, whose synthesis hasbeen described (Orlova et al., Izvestiya Sibirskogo Otdeleniya AkademiiNauk SSSR, Seriya Khimicheskikh Nauk 1994, 6, 93-7; and

3-Oxo-3-(3-phenylamino-pyridin-4-yl)-propionic acid ethyl ester, thathas been described as in intermediate in the synthesis of phenyldihydro-naphthydrine derivatives for the treatment of diabetes anddiabetes-related disorders.

In preferred embodiments, the variants have the following meanings:

R₁ is as defined above, preferably hydrogen, halo, C₁-C₄ alkyl, C₃-C₄cycloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, cyano, nitro, OR₃ or NR₃R₄;more preferably hydrogen, halo or C₁-C₄ alkyl, still more preferablyhydrogen or halo, most preferably hydrogen or F. In one embodiment, R₁is hydrogen.

R₂ is as defined above, preferably hydrogen, halo, C₁-C₄ alkyl, C₃-C₄cycloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, cyano, nitro, OR₃ or NR₃R₄;more preferably hydrogen, halo or C₁-C₂ alkyl, still more preferablyhalo or methyl, most preferably Cl, F or methyl. In one embodiment, R₂is methyl. In another embodiment, methyl is preferably furthersubstituted by 1, 2 or 3 fluorines, preferably 3 fluorines. Mostpreferably, R₂ is F.

R₉ is as defined above, preferably hydrogen, halo, C₁-C₄ alkyl, C₃-C₄cycloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, cyano, nitro, OR₃ or NR₃R₄;more preferably hydrogen, halo or C₁-C₄ alkyl, still more preferablyhydrogen, methyl or halo, most preferably hydrogen, methyl, Cl or F. Inone embodiment, R₉ is hydrogen.

R₁₀ is as defined above, preferably hydrogen, halo, C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cyano, nitro, azido;NR₄SO₂R₆; SO₂NR₃R₄; SO₂R₆; C(O)NR₃R₄; C(O)OR₃; —S(O)_(j)NR₄C(O)R₃,—C(O)NR₄S(O)_(j)R₆, OR₃ or NR₃R₄, more preferably hydrogen, halo, nitro,C₁-C₄ alkyl, O—C₁-C₄ alkyl, SO₂NR₃R₄ or C(O)NR₃R₄, still more preferablyhydrogen F, Cl, Br, nitro, methyl, O-methyl, SO₂NR₃R₄ or C(O)NR₃R₄, mostpreferably hydrogen, F, Cl, Br, methyl or O-methyl. In one embodimentR₁₀ is hydrogen. In another embodiment, R₁₀ is methyl. In yet anotherembodiment, methyl is preferably further substituted by 1, 2 or 3fluorines, preferably 3 fluorines. In preferred embodiments of R₁₀, R₃and R₄ are independently C₁-C₆ alkyl, more preferably C₁-C₄ alkyl,optionally substituted by 1 or 2 alkyl amino, dialkyl amino, amino,O-alkyl, hydroxy, or R₃ and R₄ form together a cyclic ring with 1 or 2 Natoms and optionally an O atom, said ring being optionally substitutedby 1 or 2 alkyl amino, amino, hydroxy or O-alkyl.

R₁₁ is as defined above, preferably hydrogen, halo, C₁-C₄ alkyl, C₃-C₄cycloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, cyano, nitro, OR₃ or NR₃R₄;more preferably hydrogen, halo or C₁-C₄ alkyl or O—C₁-C₄ alkyl, stillmore preferably hydrogen, methyl, O-methyl or halo, most preferablyhydrogen, methyl, Cl, Br or F. In one embodiment, R₁₁ is hydrogen. Inanother embodiment, R₁₁ is methyl. In yet another embodiment, methyl ispreferably further substituted by 1, 2 or 3 fluorines, preferably 3fluorines.

R₁₂ is as defined above, preferably hydrogen, halo, C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cyano, nitro, azido;NR₄SO₂R₆; SO₂NR₃R₄; SO₂R₆; C(O)NR₃R₄; C(O)OR₃; OR₃, NR₃R₄ or —S(C₁-C₂alkyl) substituted with 1 to 5 F, more preferably hydrogen, halo, nitro,C₁-C₄ alkyl, O—C₁-C₄ alkyl, SCF₃, SCHF₂, SCH₂F, SO₂NR₃R₄ or C(O)NR₃R₄,still more preferably hydrogen, F, Cl, Br, nitro, methyl, O-methyl,SCF₃, SCHF₂, SCH₂F, SO₂NR₃R₄ or C(O)NR₃R₄, most preferably hydrogen I,Cl, Br, SCF₃, SCHF₂, SCH₂F, methyl or O-methyl. In one embodiment R₁₂ ishydrogen. In another embodiment, R₁₂ is methyl, SCF₃, SCHF₂, SCH₂F orO-methyl, wherein methyl or O-methyl is preferably unsubstituted orfurther substituted by 1, 2 or 3 fluorines, preferably 2 or 3 fluorines.In preferred embodiments of R₁₂, R₃ and R₄ are independently C₁-C₆alkyl, more preferably C₁-C₄ alkyl, optionally substituted by 1 or 2alkyl amino, dialkyl amino, amino, O-alkyl, hydroxy, or R₃ and R₄ formtogether a cyclic ring with 1 or 2 N atoms and optionally an O atom,said ring being optionally substituted by 1 or 2 alkyl amino, amino,hydroxy or O-alkyl. Most preferably, R₁₂ is Br or I.

R₁₃ is as defined above, preferably hydrogen, halo, C₁-C₄ alkyl, C₃-C₄cycloalkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl, more preferably hydrogen, F,Cl or methyl, most preferably hydrogen or F. in one embodiment, R₁₃ ishydrogen.

R₁₄ is as defined above, preferably hydrogen, halo, C₁-C₄ alkyl, C₃-C₄cycloalkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl, more preferably hydrogen, F,Cl or methyl, most preferably hydrogen or F. In one embodiment, R₁₄ ishydrogen.

As set forth above, the variants of each of R₁, R₂ and R₉ to R₁₄ may besubstituted. In this case they can be substituted with 1 to 5,preferably 1 to 3, more preferably 1 or 2 groups independently selectedfrom oxo, halogen, cyano, nitro, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, OCH₂F,SCF₃, SCHF₂, SCH₂F, azido, NR₄SO₂R₆, SO₂NR₃R₄, C(O)R₃, C(O)OR₃, OC(O)R₃,NR₄C(O)OR₆, NR₄C(O)R₃, C(O)NR₃R₄, NR₃R₄, NR₅C(O)NR₃R₄, NR₅C(NCN)NR₃R₄,OR₃, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, preferably oxo, halogen, cyano, nitro, CF₃, CHF₂,CH₂F, OCF₃, OCHF₂, OCH₂F, SCF₃, SCHF₂, SCH₂F, azido, NR₄SO₂R₆, SO₂NR₃R₄,C(O)R₃, C(O)OR₃, OC(O)R₃, OR₃, more preferably oxo, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy or azido, mostpreferably halogen, cyano, nitro, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, OCH₂F,SCF₃, SCHF₂, SCH₂F, OH, O-methyl, NH₂ or N(methyl)₂.

R₃ is as defined above, preferably hydrogen, trifluoromethyl, C₁-C₄alkyl, G₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkylalkyl, more preferably hydrogen or C₁-C₄ alkyl most preferablyhydrogen, methyl or ethyl.

R₄ is as defined above, preferably hydrogen or C₁-C₄ alkyl, morepreferably hydrogen, methyl or ethyl.

In one preferred embodiment, R₃ and R₄ can be taken together with theatom to which they are attached to form a 4 to 7, preferably 5 or 6,membered heteroaryl or heterocyclic ring.

R₅ is as defined above, preferably hydrogen or C₁-C₄ alkyl, morepreferably hydrogen, methyl or ethyl.

In one embodiment, R₄ and R₅ can be taken together with the atom towhich they are attached to form a 4 to 7, preferably 5 or 6, memberedcarbocyclic, heteroaryl or heterocyclic ring.

R₆ is as defined above, preferably trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylalkyl, morepreferably C₁-C₄ alkyl, most preferably methyl or ethyl.

As set forth above, the variants of each of R₃, R₄, R₅, R₆ or the ringsformed by R₃ and R₄ and R₄ and R₅ may be substituted. In this case theycan be substituted with 1 to 5, preferably 1 to 3, more preferably 1 or2 groups independently selected from oxo, halogen, cyano, nitro, CF₃,CHF₂, CH₂F, OCF₃, OCHF₂, OCH₂F, azido, NR′SO₂R″″, SO₂NR″, C(O)R′,C(O)OR′, OC(O)R′, NR′C(O)OR″″, NR′C(O)R′, C(O)NR′R″, SR″″, S(O)R″″,SO₂R′, NR′R″, NR′C(O)NR″R″′, NR′C(NCN)NR″R″′, OR′, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl,preferably coxo, halogen, cyano, nitro, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂,OCH₂F, azido, NR′SO₂R″″, SO₂NR″, C(O)R′, C(O)OR′, OC(O)R′, NR′C(O)OR″″,NR′C(O)R″, C(O)NR′R″, SR″″, S(O)R″″, SO₂R′, NR′R″, NR′C(O)NR″R′″,NR′C(NCN)NR″R′″ or OR′ preferably oxo, halogen, cyano, nitro, CF₃, CHF₂,CH₂F, OCF₃, OCHF₂, OCH₂F, azido, SR″″, S(O)R″″, SO₂R′, NR′R″ or OR, mostpreferably In one embodiment, R₃ is preferably oxo, halogen, nitro,trifluoromethyl, OH, O-methyl, NH₂ or N(methyl)₂.

R′ is selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, aryl andarylalkyl, preferably hydrogen or C₁-C₄ alkyl, more preferably hydrogenor methyl.

R″ is selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, aryl andarylalkyl, preferably hydrogen or C₁-C₄ alkyl, more preferably hydrogenor methyl.

R′″ is selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, aryl andarylalkyl, preferably hydrogen or C₁-C₄ alkyl, more preferably hydrogenor methyl.

R″″ is selected from C₁-C₄ alkyl, C₁-C₄ alkenyl, aryl and arylalkyl,preferably C₁-C₄ alkyl, more preferably methyl.

Alternatively, any two of R′, R″, R′″ or R″″ can be taken together withthe atom to which they are attached to form a 4 to 10 memberedcarbocyclic, heteroaryl or heterocyclic ring, each of which isoptionally substituted with one to three groups independently selectedfrom halogen, cyano; nitro, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, OCH₂F, azido,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, preferably halogen, cyano; nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy and azido.

W is as defined above, preferably heteroaryl containing 1, 2 or 3heteroatoms, or heterocyclyl containing 1, 2, or 3 heteroatoms, morepreferably heteroaryl, each of which is unsubstituted or substituted by1 to 5, preferably 1 to 3, more preferably 1, substituents ZR₁₅, or W is—C(O)OR₁₅, —C(O)NR₄R₁₅, —C(O)NR₄OR₁₅, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₂-C₁₀ alkyl), —S(O)_(j)NR₄C(O)R₁₅, —C(O)NR₄S(O)_(j)R₆,S(O)_(j)NR₄R₁₅ or S(O)_(j)NR₄OR₁₅, more preferably W is heteroarylcontaining 1, 2, or 3, specifically 2 or 3 N atoms, C(O)NR₄OR₁₅ orS(O)₂NR₄OR₁₅.

When W is heteroaryl, it is preferably

where Z and R₁₅ are as defined above, preferably Z is a bond, NR₁₆,NR₁₆SO₂ or O, more preferably NR₁₆, wherein R₁₆ is as defined above,preferably hydrogen or C₁-C₄ alkyl, more preferably hydrogen. R₁₅ ispreferably selected from hydrogen, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₄-C₈cycloalkylalkyl, each may contain 1 N atom optionally an O atom, wherealkyl, alkenyl or cycloalkylalkyl may be further substituted by 1 or 2of OH, O—C₁-C₄ alkyl or NR′R″, where R′ and R″ are independentlyhydrogen or C₁-C₄ alkyl where R′ and R″ form a 3 to 7 membered ring with1 or 2 N atoms and optionally an O atom. Alternatively, R₁₆ and R₁₅ mayform together a 4 to 10 membered cyclic ring with 1 or 2 N atoms andoptionally an O atom, said ring being optionally substituted by 1 or 2alkyl amino, amino, hydroxy or O-alkyl. More preferably R₁₅ is C₁-C₄alkyl or C₁-C₄ alkenyl optionally substituted with 1 substitutent OH,O-Me, NH₂, N(methyl)₂ or N(ethyl)₂.

Y is O or NR′, preferably O.

Alternatively, W is preferably —C(O)OR₁₅, —C(O)NR₄R₁₅, —C(O)NR₄OR₁₅,S(O)_(j)NR₄R₁₅ or S(O)_(j)NR₄OR₁₅, more preferably —C(O)NR₄OR₁₅ orS(O)₂NR₄OR₁₅. In these cases R₁₅ is preferably as defined below.

According to Formula (II), when W is C(O)OH, then R₁, R₂, R₁₂, R₁₃ andR₁₄ are independently selected from hydrogen, halogen, cyano, nitro,azido, —NR₄C(O)OR₆, —OC(O)R₃, —NR₄S(O)_(j)R₆, —S(O)_(j)NR₃R₄,—S(O)_(j)NR₄C(O)R₃, —C(O)NR₄S(O)_(j)R₆, S(O)_(j)R₆, —NR₄C(O)R₃,—NR₅C(O)NR₃R₄, —NR₅C(NCN)NR₃R₄ and C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆alkyl), —S(O)_(j)(CR₄R₅)_(m)-aryl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O(CR₄R₅)_(m)-aryl,—NR₄(CR₄R₅)_(m)-aryl, —O(CR₄R₅)_(m)-heteroaryl, —NR₄(CR₄R₅)_(m),heteroaryl, —O(CR₄R₅)_(m)-heterocyclyl, —NR₄(CR₄R₅)_(m)-heterocyclyl and—S(C₁-C₂ alkyl) substituted with 1 to 5 F, where each alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are unsubstitutedor substituted as set forth above; —NR₃₃R₄₄, C(O)NR₃R₄₄, or OR₃₃,whereby R₃₃ is selected from hydrogen, CF₃, CHF₂, CH₂F, C₂-C₁₀ alkyl,C₂₋₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl and heterocyclyl is unsubstituted or substituted, and R₄₄ isselected from hydrogen, CF₃, CHF₂, CH₂F and C₂-C₆ alkyl. In this case,preferred embodiments of R₁, R₂, R₁₂, R₁₃ and R₁₄ are as describedabove, and R₃₃ is preferably selected from hydrogen, CF₃, CHF₂, CH₂F,C₂-C₄ alkyl and C₂₋₁₀ alkenyl, and R₄₄ is selected from hydrogen, CF₃,CHF₂, CH₂F and C₂-C₄ alkyl.

Z is as defined above, preferably a bond, NR₁₆, NR₁₆SO₂ or O, morepreferably NR₁₆.

R₁₅ is as defined above, preferably hydrogen, C₁-C₄ alkyl, C₁-C₄alkenyl, C₄-C₆ cycloalkylalkyl, more preferably C₁-C₄ alkyl or C₁-C₄alkenyl, yet more preferably C₁-C₄ alkyl. Alkyl or alkenyl may befurther substituted with 1 to 5, preferably 1, 2 or 3, more preferably 1or 2, substituents selected from OR₃ or NR′R″ wherein R₃ is selectedfrom hydrogen, C₁-C₄ alkyl or C₁-C₄ alkenyl, C₄-C₆ cycloalkylalkyl, morepreferably hydrogen, methyl or ethyl, and where R′ and R″ areindependently hydrogen or C₁-C₄ alkyl, more preferably hydrogen, methylor ethyl, still more preferably both R′ and R″ are methyl. Yet morepreferably, R₁₅ may be substituted by 1 or 2 of OH, O—C₁-C₄ alkyl orNR′R″.

Most preferably, R₁₅ is C₁-C₄ alkyl or C₁-C₄ alkenyl optionallysubstituted with 1 substitutent OH, O-Me, NH₂, N(methyl)₂ or N(ethyl)₂.

R₁₆ is as defined above, preferably hydrogen or C₁-C₄ alkyl, morepreferably hydrogen.

Alternatively, R₁₆ and R₁₅ may form together a 4 to 10, preferably 5 to6, membered cyclic ring with 1 or 2 N atoms and optionally an O atom,said ring being optionally substituted by 1 or 2 alkyl amino, amino,hydroxy or O-alkyl.

X is as defined above. In one embodiment X is N, in another embodiment Xis N→O.

m is as defined above, preferably 0, 1, 2 or 3, more preferably 0, 1 or2, most preferably 1.

j is as defined above, preferably 2.

In the above, any of the preferred definitions for each variant can becombined with the preferred definition of the other variants.

The combinations as set forth in the claims are particularly preferred.

In the above and the following, the employed terms have independentlythe meaning as described below:

Aryl is an aromatic mono- or polycyclic moiety with preferably 6 to 20carbon atoms which is preferably selected from phenyl, biphenyl,naphthyl, tetrahydronaphthyl, fluorenyl, indenyl or phenanthrenyl, morepreferably phenyl or naphthyl.

Heteroaryl is an aromatic moiety having 6 to 20 carbon atoms with atleast one ring containing a heteroatom selected from O, N and/or S, orheteroaryl is an aromatic ring containing at least one heteroatomselected from O, N and/or S and 1 to 6 carbon atoms. Preferably,heteroaryl contains 1 to 4, more preferably 1, 2 or 3 heteroatomsselected from O and/or N and is preferably selected from pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl. Spiro moieties are also includedwithin the scope of this definition. Preferred heteroaryl includepyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, isoxazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl.Heteroaryl groups are optionally mono-, di-, or trisubstituted with,e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl,and hydroxy.

Heterocyclyl is a saturated or unsaturated ring containing at least oneheteroatom selected from O, N and/or S and 1 to 6 carbon atoms.Preferably, heterocyclyl contains 1 to 4, more preferably 1, 2 or 3heteroatoms selected from O and/or N and is preferably selected frompyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl,imidazolidinyl, azetidin-2-one-1-yl, pyrrolidin-2-one-1-yl,piperid-2-one-1-yl, azepan-2-one-1-yl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl andquinolizinyl. Spiromoieties are also included within the scope of thisdefinition.

Carbocyclyl is a monocyclic or polycyclic ring system of 3 to 20 carbonatoms which may be saturated, unsaturated or aromatic.

Alkyl is a saturated hydrocarbon moiety, namely straight chain orbranched alkyl having 1 to 10, preferably 1 to 8 carbon atoms, morepreferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,neopentyl, hexyl or heptyl.

Cycloalkyl is an alkyl ring having 3 to 10, preferably 3 to 8 carbonatoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Alkenyl is an unsaturated hydrocarbon moiety with one or more doublebonds, preferably one double bond, namely straight chain or branchedalkenyl having 1 to 10, preferably 2 to 8 carbon atoms, more preferably2 to 4 atoms, such as vinyl, allyl, methallyl, buten-2-yl, buten-3-yl,penten-2-yl, penten-3-yl, penten-4-yl, 3-methyl-but-3-enyl,2-methyl-but-3-enyl, 1-methyl-but-3-enyl, hexenyl or heptenyl.

Alkynyl is an unsaturated hydrocarbon moiety with one or more triplebonds, preferably one triple bond, namely straight chain or branchedalkynyl having 1 to 10, preferably 2 to 8 carbon atoms, more preferably2 to 4 atoms, such as ethynyl, propynyl, butyn-2-yl, butyn-3-yl,pentyn-2-yl, pentyn-3-yl, pentyn-4-yl, 2-methyl-but-3-ynyl,1-methyl-but-3-ynyl, hexynyl or heptynyl.

Halo or halogen is a halogen atom preferably selected from F, Cl, Br andI, preferably F, Cl and Br.

In the definitions cycloalkylalkyl, arylalkyl, heretoarylalkyl andheterocyclylalkyl it is contemplated that cycloalkyl, aryl, heretoaryland heterocyclyl are bonded via an alkylene moiety. This alkylene moietymay be a straight chain or branched chain group. Said alkylene moietypreferably has 1 to 6 carbon atoms. Examples thereof include methylene,ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene,iso-propylene, sec.-butylene, tert.-butylene, 1,1-dimethyl propylene,1,2-dimethyl propylene, 2,2-dimethyl propylene, 1,1-dimethyl butylene,1,2-dimethyl butylene, 1,3-dimethyl butylene, 2,2-dimethyl butylene,2,3-dimethyl butylene, 3,3-dimethyl butylene, 1-ethyl butylene, 2-ethylbutylene, 3-ethyl butylene, 1-n-propyl propylene, 2-n-propyl propylene,1-iso-propyl propylene, 2-iso-propyl propylene, 1-methyl pentylene,2-methyl pentylene, 3-methyl pentylene and 4-methyl pentylene. Morepreferably, said alkylene moiety has 1 to 3 carbon atoms, such asmethylene, ethylene, n-propylene and iso-propylene. Most preferred ismethylene.

“Carboxy refers to the group —C(O)OR, where R includes hydrogen or“C₁-C₆-alkyl”.

“Acyl” refers to the group —C(O)R where R includes “C₁-C₆-alkyl”,“aryl”, “heteroaryl”, “C₃-C₈-cycloalkyl”, “C₃-C₈-heterocycloalkyl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”. “Acyloxy” refers to thegroup —OC(O)R where R includes “C₁-C₆-alkyl”, “aryl”, “hetero-aryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“Aryl acyl” refers to aryl groups having an acyl substituent, including2-acetylphenyl and the like.

“Heteroaryl acyl” refers to heteroaryl groups having an acylsubstituent, including 2-acetylpyridyl and the like.

“Alkoxy” refers to the group —O—R where R includes “C₁-C₆-alkyl”,“C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“Heterocycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₂-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”. Preferred alkoxy groups include by way of example,methoxy, ethoxy, phenoxy and the like.

“Alkoxycarbonyl” refers to the group C(O)OR where R includes“C₁-C₆-alkyl” or “aryl” or “heteroaryl” or “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”.

“Alkoxycarbonylamino” refers to the group —NR′C(O)OR where R includes“C₁-C₆-alkyl” or “aryl” or “heteroaryl” or “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl” a and R′ includes hydrogen or “C₁-C₆-alkyl

“Aminocarbonyl” refers to the group C(O)NRR′ where each R, R′ includesindependently hydrogen or C₁-C₆-alkyl or aryl or heteroaryl or“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl hetero-aryl”.

“Acylamino” refers to the group —NR(CO)R′ where each R. R′ isindependently hydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“Sulfonyloxy” refers to a group —OSO₂—R wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted with halogens, e.g., an—OSO₂—CF₃ group, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“Sulfonyl” refers to group “—SO₂—R” wherein R is selected from H,“aryl”, “heteroaryl”, “C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted withhalogens, e.g., an —SO₂—CF₃ group, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“Sulfinyl” refers to a group “—(O)—R” wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted with halogens, e.g., an —SO—CF₃group, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“Heterocycloalkyl”, “heterocycloalkyl”³, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“Sulfanyl” refers to groups —S—R where R includes H, “C₁-C₆-alkyl”,“C₁-C₆-alkyl” optionally substituted with halogens., e.g a —S—CF₃ group,“C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”. Preferredsulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.

“Sulfonylamino” refers to a group —NRSO₂—R′ where each R, R′ includesindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“Aminosulfonyl” refers to a group —SO₂—NRR′ where each R, R′ includesindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“Amino” refers to the group —NRR′ where each R, R′ is independentlyhydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “Heterocycloalkyl”, “heterocycloalkyl”, “aryl”,“heteroaryl”, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”,“C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenyl heteroaryl”, “C₂-C₈-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”, and where R and R′, together with the nitrogen atomto which they are attached, can optionally form a 3-8-memberedhetero-cycloalkyl ring.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “alkoxy”, “aryl” and “heteroaryl” etc.groups can optionally be independently substituted with from 1 to 5substituents selected from the group consisting of “C₁-C₆-alkyl”,“C₁-C₆-alkyl aryl”, “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl”,“C₂-C₆-alkynyl”, primary, secondary or tertiary amino groups orquaternary ammonium moieties, “acyl”, “acyloxy”, “acylamino”,“aminocarbonyl”, “alkoxycarbonylamino”, “alkoxycarbonyl”, “aryl”,“aryloxy”, “heteroaryl”, “heteroaryloxy”, carboxyl, cyano, halogen,hydroxy, nitro, sulfanyl, sulphoxy, sulphonyl, sulfonamide, alkoxy,thioalkoxy, trihalomethyl and the like. Within the framework of thisinvention, said “substitution” is meant to also comprise situationswhere neighboring substituents undergo ring closure, in particular whenvicinal functional substituents are involved, thus forming e.g. lactams,lactons, cyclic anhydrides, but also acetals, thioacetals, animalsformed by ring closure for instance in an effort to obtain a protectivegroup.

Compounds according to formula (I) include in particular those of thegroup consisting of:

Preferred embodiments of the compounds according to present inventionare shown in scheme 1.

The compounds of the present invention can be in the form of a prodrugcompound. “Prodrug compound” means a derivative that is converted into acompound according to the present invention by a reaction with anenzyme, gastric acid or the like under a physiological condition in theliving body, e.g. by oxidation, reduction, hydrolysis or the like, eachof which is carried out enzymatically. Examples of the prodrug arecompounds, wherein the amino group in a compound of the presentinvention is acylated, alkylated or phosphorylated to form, e.g.,eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein thehydroxyl group is acylated, alkylated, phosphorylated or converted intothe borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy,fumaryloxy, alanyloxy or wherein the carboxyl group is esterified oramidated. These compounds can be produced from compounds of the presentinvention according to well-known methods. Other examples of the prodrugare compounds, wherein the carboxylate in a compound of the presentinvention is for example converted into an alkyl-, aryl-, choline-,amino, acyloxymethylester, linolenoyl-ester.

Metabolites of compounds of the present invention are also within thescope of the present invention.

Where tautomerism, like e.g. keto-enol tautomerism, of compounds of thepresent invention or their prodrugs may occur, the individual forms,like e.g. the keto and enol form, are claimed separately and together asmixtures in any ratio. Same applies for stereoisomers, like e.g.enantiomers, cis/trans isomers, conformers and the like.

If desired, isomers can be separated by methods well known in the art,e.g. by liquid chromatography. Same applies for enantiomers by usinge.g. chiral stationary phases. Additionally, enantiomers may be isolatedby converting them into diastereomers, i.e. coupling with anenantiomerically pure auxiliary compound, subsequent separation of theresulting diastereomers and cleavage of the auxiliary residue.Alternatively, any enantiomer of a compound of the present invention maybe obtained from stereoselective synthesis using optically pure startingmaterials.

The compounds of the present invention can be in the form of apharmaceutically acceptable salt or a solvate. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, includinginorganic bases or acids and organic bases or acids. In case thecompounds of the present invention contain one or more acidic or basicgroups, the invention also comprises their correspondingpharmaceutically or toxicologically acceptable salts, in particulartheir pharmaceutically utilizable salts. Thus, the compounds of the ofthe present invention which contain acidic groups can be present onthese groups and can be used according to the invention, for example, asalkali metal salts, alkaline earth metal salts or as ammonium salts.More precise examples of such salts include sodium salts, potassiumsalts, calcium salts, magnesium salts or salts with ammonia or organicamines such as, for example, ethylamine, ethanolamine, triethanolamineor amino acids. Compounds of the present invention which contain one ormore basic groups, i.e. groups which can be protonated, can be presentand can be used according to the invention in the form of their additionsalts with inorganic or organic acids. Examples for suitable acidsinclude hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuricacid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid,lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid,pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelicacid, fumaric acid, maleic acid, malic acid, sulfaminic acid,phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid,citric acid, adipic acid, and other acids known to the person skilled inthe art. If the compounds of the present invention simultaneouslycontain acidic and basic groups in the molecule, the invention alsoincludes, in addition to the salt forms mentioned, inner salts orbetaines (zwitterions). The respective salts can be obtained bycustomary methods which are known to the person skilled in the art like,for example by contacting these with an organic or inorganic acid orbase in a solvent or dispersant, or by anion exchange or cation exchangewith other salts. The present invention also includes all salts of thecompounds of the present invention which, owing to low physiologicalcompatibility, are not directly suitable for use in pharmaceuticals butwhich can be used, for example, as intermediates for chemical reactionsor for the preparation of pharmaceutically acceptable salts.

Furthermore, the present invention provides pharmaceutical compositionscomprising a compound of the present invention, or a prodrug compoundthereof, or a pharmaceutically acceptable salt or solvate thereof asactive ingredient together with a pharmaceutically acceptable carrier.

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may additionallycomprise one or more other compounds as active ingredients like one ormore additional compounds of the present invention, or a prodrugcompound or other MEK inhibitors.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In one embodiment, said compounds and pharmaceutical composition are forthe treatment of cancer such as brain, lung, squamous cell, bladder,gastic, pancreatic, breast, head, neck, renal, kidney, ovarian,prostate, colorectal, oesohageal, testicular, gynecological or thyroidcancer. In another embodiment, said pharmaceutical composition is forthe treatment of a noncancerous hyperproliferative disorder such asbenign hyperplasia of the skin (e.g., psoriasis), restenosis, orprostate (e.g. benign prostatic hypertrophy (BPH)).

The invention also relates to the use of compounds according to formula(I) or formula (II) for the preparation of a medicament for thetreatment of hyperproliferative diseases related to the hyperactivity ofMEK as well as diseases modulated by the MEK cascade in mammals, ordisorders mediated by aberrant proliferation, such as cancer.

The invention also relates to a compound or pharmaceutical compositionfor the treatment of pancreatitis or kidney disease (includingproliferative glomerulonephritis and diabetes induced renal disease) orpain in a mammal which comprises a therapeutically effective amount of acompound of the present invention, or a pharmaceutically acceptablesalt, prodrug or hydrate thereof, and a pharmaceutically acceptablecarrier. The invention also relates to a compound or pharmaceuticalcomposition for the prevention of blastocyte implantation in a mammalwhich comprises a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, and a pharmaceutically acceptable carrier. Theinvention also relates to a compound or pharmaceutical composition fortreating a disease related to vasculogenesis or angiogenesis in a mammalwhich comprises a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, and a pharmaceutically acceptable carrier.

In one embodiment, said compound or pharmaceutical composition is fortreating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,inflammatory bowel disease, atherosclerosis, skin diseases such aspsoriasis, excema, and sclerodema, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangicma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

The invention also relates to of the use for treating ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof. In one embodiment, said use relates to the treatment ofcancer such as brain, lung, squamous cell, bladder, gastic, pancreatic,breast, head, neck, renal, kidney, ovarian, prostate, colorectal,oesohageal, testicular, gynecological or thyroid cancer. In anotherembodiment, said use relates to the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The invention also relates to a use for the treatment of ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, in combination with an anti-tumor agent selected fromthe group consisting of mitotic inhibitors, alkylating agents,antimetabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors,biological response modifiers, antihormones, angiogenesis inhibitors,and anti-androgens.

The invention also relates to a use of treating pancreatitis or kidneydisease or pain in a mammal that comprises administering to said mammala therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug or hydratethereof. The invention also relates to a use of preventing blastocyteimplantation in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a use of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof. In one embodiment, said method is for treating adisease selected from the group consisting of tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, excema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer. Patients thatcan be treated with compounds of the present invention, orpharmaceutically acceptable salts, prodrugs and hydrates of saidcompounds, according to the methods of this invention include, forexample, patients that have been diagnosed as having psoriasis,restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML,pancreatic cancer, skin cancer, cancer of the head and neck, cutaneousor intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system (e.g., cancer of the thyroid, parathyroid or adrenalglands), sarcomas of soft tissues, cancer of the urethra, cancer of thepenis, prostate cancer, chronic or acute leukemia, solid tumors ofchildhood, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter (e.g., renal cell carcinoma, carcinoma of the renalpelvis), or neoplasms of the central nervous system (e.g., primary CNSlymphona, spinal axis tumors, brain stem gliomas or pituitary adenomas).

This invention also relates to a compound or pharmaceutical compositionfor inhibiting abnormal cell growth in a mammal which comprises anamount of a compound of the present invention, or a pharmaceuticallyacceptable salt or solvate or prodrug thereof, in combination with anamount of a chemotherapeutic, wherein the amounts of the compound, salt,solvate, or prodrug, and of the chemotherapeutic are together effectivein inhibiting abnormal cell growth. Many chemotherapeutics are presentlyknown in the art. In one embodiment, the chemotherapeutic is selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, angiogenesis inhibitors, andanti-androgens. This invention further relates to a method forinhibiting abnormal cell growth in a mammal or treating ahyperproliferative disorder which method comprises administering to themammal an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate or prodrug thereof, incombination with radiation therapy, wherein the amounts of the compound,salt, solvate, or prodrug, is in combination with the radiation therapyeffective in inhibiting abnormal cell growth or treating thehyperproliferative disorder in the mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound of the invention in this combination therapy can be determinedas described herein. It is believed that the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation whichcomprises administering to the mammal an amount of a compound of thepresent invention or pharmaceutically acceptable salt or solvate orprodrug thereof, which amount is effective is sensitizing abnormal cellsto treatment with radiation. The amount of the compound, salt, orsolvate in this method can be determined according to the means forascertaining effective amounts of such compounds described herein. Theinvention also relates to a method of and to a pharmaceuticalcomposition of inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

In practical use, the compounds of the present invention can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of the present invention may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds of thepresent invention are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing cancer, inflammation or other proliferativediseases for which compounds of the present invention are indicated,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.1milligram to about 100 milligram per kilogram of animal body weight,preferably given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. For most large mammals, thetotal daily dosage is from about 1.0 milligrams to about 1000milligrams, preferably from about 1 milligram to about 50 milligrams. Inthe case of a 70 kg adult human, the total daily dose will generally befrom about 7 milligrams to about 350 milligrams. This dosage regimen maybe adjusted to provide the optimal therapeutic response.

Some abbreviations that may appear in this application are as follows.

Abbreviations

Designation

-   b Broad peak-   CDI N,N-Carbonyldiimidazole-   d Doublet-   DCM Dichloromethane-   dd double doublet-   DIPEA N-Ethyldiisopropylamine-   DMF N,N-Dimethylformamide-   EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   HPLC High pressure liquid chromatography-   LiHMDS. Lithium hexamethyldisilazide-   MCPBA 3-Chloroperoxybenzoic acid-   NMR Nuclear Magnetic Resonance-   PG Protecting group-   PyBOP Benzotriazole-1-yl-oxy-trispyrrolidinophosphonium    hexafluorophosphate-   q Quartett-   rt Retention time-   s Singlet-   tert Tertiary-butyl-   TFA Trifluoroacetic acid-   THF Tetrahydrofurane-   TLC Thin Layer Chromatography

The compounds of the present invention can be prepared according to theprocedures of the following Schemes and Examples, using appropriatematerials and are further exemplified by the following specificexamples. Moreover, by utilizing the procedures described herein, inconjunction with ordinary skills in the art, additional compounds of thepresent invention claimed herein can be readily prepared. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. The examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds. The instant compoundsare generally isolated in the form of their pharmaceutically acceptablesalts, such as those described above. The amine-free bases correspondingto the isolated salts can be generated by neutralization with a suitablebase, such as aqueous sodium hydrogencarbonate, sodium carbonate, sodiumhydroxide and potassium hydroxide, and extraction of the liberatedamine-free base into an organic solvent, followed by evaporation. Theamine-free base, isolated in this manner, can be further converted intoanother pharmaceutically acceptable salt by dissolution in an organicsolvent, followed by addition of the appropriate acid and subsequentevaporation, precipitation or crystallization.

An illustration of the preparation of compounds of the present inventionis shown in schemes 2 and 3. Unless otherwise indicated in the schemes,the variables have the same meaning as described above.

The examples presented below are intended to illustrate particularembodiments of the invention.

Scheme 2 illustrates the synthesis of compounds in the presentinvention. In step 1 the aniline 1 is reacted with 3-fluoro isonicotinicacid in an inert solvent, preferable THF, by addition af a base,preferably but not limited to LiHMDS. In step 2 the 3-anilinoisonicotinic acid 2 is coupled with an O-alkyl hydroxalamine using anappropriate coupling reagent including but not limited to PyBOP; EDC orDCC in a suitable organic solvents like for example DMF, THF or DCM toyield hydroxamate 3. Compound 3 is then converted into the correspondingpyridine N-oxide 4 by using oxidation reagents as for example MCPBA orperacetic acid in a suitable solvent like for example THF or DCM.

Suitable anilines and isonicotinic acid derivatives are commerciallyavailable from Sigma-Aldrich Chemie GmbH, Munich, Germany or from AcrosOrganics, Belgium or from Fisher Scientific GmbH, 58239 Schwerte,Germany or can be routinely prepared by procedures described in “March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure”, 5thEdition; John Wiley & Sons. Scheme 3 illustrates the preparation ofcompounds of the present invention where W is heterocyclic. In step 1the 3-anilino isonicotinic acid derivative 5 is reacted withpentafluorophenyl trifluoroacetate and a base, for example pyridine, togive the active ester 6 which is further converted in step 2 tohydrazide 7 by reacting it with hydrazine or hydrazine hydrate in aninert solvent such as DCM, DMF or THF. Reaction of 7 with CDI or anysuitable carbonate equivalent in a preferred solvent such as DMF or DCMfor example then gives Oxadiazolone 8, which forms N-substiutuedhydrazinecarboxamides 9 when treated with a substituted amine inethanol. Cyclization is achieved by addition of triphenylphosphine and abase such as triethylamine or DIPEA in an inert solvent like CCl₄ forexample to give compound 10.

Compounds with other variants in the position of W can be prepared byderivatizing the COOH group appropriately as known to the person skilledin the art as described in Theophil Eicher, Siegfried Hauptmann “TheChemistry of Heterocycles; Structures, Reactions, Synthesis andApplication”, 2^(nd) edition, Wiley-VCH 2003. The introduction ofalternative heterocyclic or heteroaryl groups is exemplified e.g. in WO03/077855 and WO 01/05391.

Unless otherwise noted, all non-aqueous reactions were carried outeither under an argon or nitrogen atmosphere with commercial drysolvents. Compounds were purified using flash column chromatographyusing Merck silica gel 60 (230-400 mesh), or by reverse phasepreparative HPLC using a Reprosil-Pur ODS3, 5 μm, 20×125 mm column withShimadzu LC8A-Pump and SPD-10Avp UVN is diode array detector. The ¹H-NMRspectra were recorded on a Varian VXR-S (300 MHz for ¹H-NMR) usingd₆-dimethylsulfoxide or d₄-methanol as solvent; chemical shifts arereported in ppm relative to tetramethylsilane. Analytical LC/MS wasperformed using Reprosil-Pur ODS3, 5 μM, 1×60 mm columns at a flow rateof 250 μl/min, sample loop 2.5 μl; retention times are given in minutes.Methods are: (I) runs on a LC10Advp-Pump (Shimadzu) with SPD-M10AvpUV/Vis diode array detector and QP2010 MS-detector in ESI+ modus withUV-detection at 214, 254 and 275 nm with a gradient of 15-95%acetonitrile (B) in water (A) (0.1% formic acid), 5 min. lineargradient; (II) idem but linear gradient 8 min 1-30% B; (III) idem butlinear gradient 8 min 10-60% B; (IV) idem but linear gradient 8 min15-99% B; (V) idem but linear gradient 5 min 10-90% B; (VI) idem butlinear gradient 5 min 5-95% B.

EXAMPLES

The examples presented below are intended to illustrate particularembodiments of the invention, and are not intended to limit the scope ofthe specification or the claims in any way.

Example 1 3-[(2,4-Dichlorophenyl)amino]isonicotinic acid (2a)

2,4-Dichloraniline (162 mg, 1.00 mmol) and 3-fluoropyridine-4-carboxylicacid (141 mg, 1.00 mmol) were dissolved in dry THF (6.0 ml) under argonand the mixture was cooled to −78° C. A solution of LiHMDS (1.0M in THF,3.5 ml) was added and the reaction mixture was allowed to warm toambient temperature. After 18 h the reaction was quenched by adding asolution of HCl in dioxane (4.0M, 2.0 ml). The volatiles were removed invacuo and the crude material was purified by flash chromatography usingsilica gel and a gradient of 0-10% methanol in DCM as eluent to give 204mg (721 μmol; 72% yield) of pure desired product.

LC-MS (method I): rt=2.98 min; m/z [M+H]⁺ 282.9; ¹H-NMR (300 MHz,DMSO-d₆): δ=7.72 (1H, dd, J=2.2 Hz, J=8.8 Hz); 7.48 (1H, d, J=8.8 Hz);7.53 (1H, d, J=2.9 Hz); 7.71 (1H, d, J=4.4 Hz); 7.99 (1H, d, J=5.1 Hz);8.46 (1H, s); 11.3 (1H, b).

Example 2 3-[(4-Bromo-2-methylphenyl)amino]isonicotinic acid (2b)

4-Bromo-2-methylaniline (186 mg, 1.00 mmol) and3-fluoropyridine-4-carboxylic acid (141 mg, 1.00 mmol) were dissolved indry THF (6.0 ml) under argon and the mixture was cooled to −78° C. Asolution of LiHMDS (1.0M in THF, 3.5 ml) was added and the reactionmixture was allowed to warm to ambient temperature. After 24 h thereaction was quenched by adding a solution of HCl in dioxane (4.0M, 2.0ml). The volatiles were removed in vacuo and the crude material waspurified by flash chromatography using silica gel and a gradient of0-10% methanol in DCM as eluent to give 215 mg (701 μmol; 70% yield) ofpure desired product.

LC-MS (method I): rt 1.57 min; m/z [M+H]⁺ 306.7; ¹H-NMR (300 MHz,DMSO-d₆): δ=2.23 (3H, s); 3.62 (1H, b); 7.27 (2H, s); 7.38 (1H, s); 7.65(1H, d, J=4.1 Hz); 7.91 (1H, d, J=7.9 Hz); 8.45 (1H, s).

Example 3 3-[(4-Iodo-2-methylphenyl)amino]isonicotinic acid (2c)

4-Iodo-2-methylaniline (233 mg, 1.00 mmol) and3-fluoropyridine-4-carboxylic acid (141 mg, 1.00 mmol) were dissolved indry THF (6.0 ml) under argon and the mixture was cooled to −78° C. Asolution of LiHMDS (1.0M in THF, 3.5 ml) was added and the reactionmixture was allowed to warm to ambient temperature. After 36 h thereaction was quenched by adding solid NH₄Cl. After filtration thevolatiles were removed in vacuo and the crude material was purified byflash chromatography using silica gel and a gradient of 0-10% methanolin DCM as eluent to give 208 mg (588 μmol; 59% yield) of pure desiredproduct.

LC-MS (method I): rt 1.69 min; m/z [M+H]⁺ 395.8; ¹H-NMR (300 MHz,DMSO-d₆): δ=2.20 (3H, s); 3.80 (1H, b); 7.15 (1H, d, J=8.8 Hz); 7.20(1H, b); 7.48 (1H, dd, J=8.1 Hz, J=2.2 Hz); 7.61 (1H, d, J=1.5 Hz); 7.66(1H, d, J=5.1 Hz); 7.97 (1H, d, J=4.4 Hz); 8.30 (1H, s).

Example 4 3-[(4-Bromo-2-methylphenyl)amino]-N-ethoxyisonicotinamide (3b)

3-[(4-Bromo-2-methylphenyl)amino]isonicotinic acid 2b (320 mg, 1.04mmol) was dissolved in 15 ml dry DMF followed by the addition of DIPEA(2.08 mmol, 373 μl), ByBOP (1.25 mmol, 651 mg) and O-ethylhydroxylaminehydrochloride (2.08 mmol, 203 mg). The mixture was stirred for 2 h andthe volatiles were removed in vacuo. The crude material was purified byflash chromatography using silica gel and a gradient of 0-5% methanol inDCM as eluent to give 280 mg (800 μmol; 77% yield) of pure desiredproduct.

LC-MS (method I): rt 1.90 min; m/z [M+H]⁺ 351.9; ¹H-NMR (300 MHz,DMSO-d₆): δ=1.20 (3H, t, J=6.6 Hz); 2.21 (3H, s); 3.91 (2H, q, J=6.6Hz); 7.20 (1H, d, J=8.8 Hz); 7.34 (1H, dd, J=8.8 Hz, J=2.2 Hz); 7.42(1H, d, J=5.1 Hz); 7.47 (1H, d, J=2.2 Hz); 8.08 (1H, d, J=5.1 Hz); 8.35(1H, s); 8.70 (1H, b).

Example 5 N-Ethoxy-3-[(4-iodo-2-methylphenyl)amino]isonicotinamide (3c)

3-[(4-iodo-2-methylphenyl)amino]isonicotinic acid 2c (60 mg, 0.17 mmol)was dissolved in 6 ml dry DMF followed by the addition of DIPEA (0.20mmol, 37 μl), ByBOP (0.20 mmol, 107 mg) and O-ethylhydroxylaminehydrochloride (0.34 mmol, 34 mg). The mixture was stirred for 4 h andthe volatiles were removed in vacuo. The crude material was purified bypreparative reversed phase HPLC to give 36 mg (91 μmol; 53% yield) ofpure desired product.

LC-MS (method I): rt 2.14 min; m/z [M+H]⁺ 397.9; ¹H-NMR (300 MHz,DMSO-d₆): δ=1.20 (3H, t, J=7.3 Hz); 2.19 (3H, s); 3.40 (b); 3.90 (2H, q,J=7.3 Hz); 7.07 (1H, d, J=8.8 Hz); 7.42 (1H, d, J=5.1 Hz); 7.48 (1H, 2,J=7.3 Hz); 8.08 (1H, d, J=4.4 Hz); 8.37 (1H, s); 8.71 (1H, b).

Example 6 3-[(4-Bromo-2-methylphenyl)amino]-N-ethoxyisonicotinamide1-oxide (4b)

3-[(4-Bromo-2-methylphenyl)amino]-N-ethoxyisonicotinamide 3b (80.0 mg,0.228 mmol) was dissolved in 4 ml dry DCM and 3-chloroperbenzoic acid(73% pure, 60 mg) was added at ambient temperature. After 2 h thesolvent was removed in vacuo and the crude material was purified byflash chromatography using silica gel and a gradient of 0-10% methanolin DCM as eluent to give 37 mg (101 μmol; 44% yield) of pure desiredproduct.

LC-MS (method II): rt 4.47 min; m/z [M+H]⁺ 366.0; ¹H-NMR (300 MHz,DMSO-d₆): δ=1.22 (3H, t, J=7.3 Hz); 2.21 (3H, s); 3.94 (2H, q, J=7.3Hz); 7.27 (1H, d, J=8.8 Hz); 7.41 (1H, dd, J=8.8 Hz, J=2.2 Hz); 7.51(1H, d, J=6.6 Hz); 7.55 (1H, dd, J=10.3 Hz, J=2.2 Hz); 7.68 (1H, dd,J=6.6 Hz, J=2.2 Hz); 9.31 (1H, b).

General Method 1 starts with the reaction of various 3-halogenatedisonicotonic acids with substituted anilines in the presence of base.The resulting acids were further derivatized by reaction with 1,1carbonyldiimidazole in DMSO followed by addition of the desirednucleophile.

Intermediate 1

3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (R=fluoro)

A mixture of 2-fluoro-4-iodoaniline (20.0 g, 84.38 mmol) in dry THF (80mL) was cooled to −67° C. (dry ice/IPA bath) under nitrogen, prior toslow addition of 1.0 M lithium bis(trimethylsilyl)amide (255 mL, 255mmol) via addition funnel, at a rate that kept the internal temp below−59° C. (˜2 h). After final addition, the yellow-green slurry wasstirred for 30 min and then treated with 2-fluoroisonicotinic acid (8.0g, 56.69 mmol). The bath was not removed, but the contents were allowedto slowly warm to room temp. After 4 days, the dark slurry was pouredinto a biphasic mixture of aqueous 2.0 N sodium hydroxide (1000 mL) andethyl acetate (150 mL). The aqueous layer was separated and the organicswere again extracted with base (1000 mL). The pH of the two aqueouslayers was adjusted to ˜2 with concentrated hydrochloric acid. A yellowsolid precipitated, which was filtered. The resultant yellow cake waswashed with water (2×400 mL) and dried under high vacuum at 40° C.(17-19 g). LC/MS [(5.2 min; 359 (M+1)].

Intermediate 2

3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (R=chloro):synthesized as intermediate 1 by reacting 15.7 mmol of2-chloro-4-iodoaniline with 23.55 mmol 2-fluoroisonicotinic acid. LC/MS[(5.9 min; 376 (M+1)].

Intermediate 3

3-[(2-methyl-4-iodophenyl)amino]isonicotinic acid (R=methyl):synthesized as intermediate 1 by reacting 4.7 mmol of2-methyl-4-iodoaniline with 7.0 mmol 2-fluoroisonicotinic acid. LC/MS[(5.3 min; 355 (M+1)]. See detailed procedure in Example 3.

Synthesis of MEK Inhibitors; General Procedure for Carboxylic AcidDerivatization of 3-phenylamino-isonicotinic acids

The carboxylic acid (see intermediates 1-3) (0.2-8 mmol) and CDI (1,1carbonyldiimidazole) (1.3 eq) in dry DMSO (10-20 volumes) was stirred atroom temp (13-18 h). The dark-yellow solution was then treated with asubstituted amine, substituted hydrazine or O-substituted hydroxylamine(1-2 eq). The contents were stirred at room temp for 4-18 h and theresultant dark-yellow solution was poured into ethyl acetate, washedwith brine and concentrated.

Method for the synthesis of 3-phenylamino-1-oxy-isonicotinic acidderivatives

1-oxy derivatives were synthesized in a similar manner. First step inthis synthesis was the N-oxidation of 3-fluoroisonicotinic acid. Thesubsequent steps were performed as previously described under GeneralMethod 1. Procedural details for this synthesis are as following:

3-fluoroisonicotinic acid 1-oxide

To a solution of 3-fluoroisonicotinic acid (5.0 g, 35.33 mmol) in aceticacid (25 ml) was added hydrogen peroxide (6 ml). The reaction mixturewas stirred at 70-80° C. overnight. The solvent was removed to obtain5.5 g of 3-fluoroisonicotinic acid 1-oxide in quantitative yield.

3-(2-Fluoro-4-iodo-phenylamino)-1-oxy-isonicotinic acid

Lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (62 ml, 62.0 mmol) wasadded to a solution of 2-fluoro-4-iodoaniline (7.24 g, 30.55 mmol) inTHF at −78° C. The mixture was stirred for 90 min at −78° C., thenanother 1.2 equiv. of lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (3r1ml 31.0 mmol) was added, following by 3-fluoroisonicotinic acid 1-oxide(4.0 g, 25.46 mmol). The reaction mixture was warmed to room temperatureand stirred overnight. The solvent was evaporated, and water was added(50 ml). The pH of the aqueous layer was adjusted to <3, and washed withether (20 ml×2). The product precipitated as a yellow solid. It wasfiltered, and dried to get 3.50 g of material. (36%) of3-(2-Fluoro-4-iodo-phenylamino)-1-oxy-isonicotinic acid. LC/MS: [7.32min; 374 (M+1)]

3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide 1-oxide

3-(2-Fluoro-4-iodo-phenylamino)-1-oxy-isonicotinamide was synthesizedaccording to the general procedure of Method 1 as, outlined above,starting with 110 mg (0.29 mmol) of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid 1-oxide and 56 mg(0.74 mmol) of ammonium acetate LC/MS: [7.32 min; 375 (M+1)]

Method for the Synthesis of 2-Bromo-3-Phenylamino-Isonicotinic AcidDerivatives

2-Bromo-3-phenylamino-isonicotinic acid derivatives were synthesized ina similar manner. A typical procedure for the synthesis of such analogsfollows below:

2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid

Lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (11.9 ml, 1.00 M, 11.82mmol) was added to a solution of 2-fluoro-4-iodoaniline (1.40 g, 5.91mmol) at −78° C. The pale green colored solution was stirred for 1½ h at−78° C. Then, lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (5.45 ml,1.00 M, 5.45 mmol) was added followed by 2-bromo-5-fluoroisonicotinicacid (1.00 g, 4.55 mmol) in THF (5 ml). The dark colored homogeneousmixture was warmed to room temperature and stirred overnight. The crudewas diluted with EtOAc (300 ml). Then, it washed with dilute HClsolution (20 ml), H₂O (20 ml), dried and purified on Flashmaster IIusing a 100 g cartridge to obtain 1.18 g (59%) of2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid.

LC/MS: 7.43 min, 438 (M+1)

2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide

To a solution of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinicacid

(145.0 mg, 0.33 mmol) in N,N-dimethylformamide (1.50 ml).1,1′-carbonylbis(1H-imidazole) (60 mg 0.36 mmol) was added, and themixture was stirred at room temperature for 7 hours to obtain ahomogeneous solution. Ammonium acetate (65 mg 0.83 mmol) was added, andstirred for 2 h. Water (10 ml) was added, and the precipitated solid wasfiltered, washed with hot methanol to obtain2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide as an yellowsolid (85 mg, 58%) LC/MS: [9.59 min; 436, 438]

Method for the Synthesis of 2-Alkyl-3-Phenylamino-Isonicotinic AcidDerivatives

A typical procedure for the synthesis of2-alkyl-3-phenylamino-isonicotinic acid derivatives:

Methyl 2-bromo-5-fluoroisonicotinate

To a solution of 2-bromo-5-fluoroisonicotinic acid (1.5 g, 6.82 mmol) inmethanol (75 ml), thionyl dichloride (2.5 ml, 34.09 mmol) was addeddrop-wise. The reaction mixture was stirred overnight. The solvent wasremoved under high vacuum. The residual solid was distilled at 90° C.under vacuum to get 1.3 g (81%) of pure methyl2-bromo-5-fluoroisonicotinate:

Methyl 5-fluoro-2-methylisonicotinate

To a solution of methyl 2-bromo-5-fluoroisonicotinate (1.0 g, 4.27 mmol)in tetrahydrofuran (25 ml) tetrakis(triphenylphosphine)palladium (495.0mg, 0.43 mmol) was added. The mixture was stirred for 10 min, and thentrimethylaluminum (5.13 ml, 1.00 M in heptane, 5.13 mmol) was added. Themixture was refluxed for 4 h, and the reaction was monitored by TLC (10%EtOAc-Hexane). Then, the reaction was diluted with EtOAc (75 ml) and afew drops of saturated. ammonium chloride were added. The mixture wasfiltered through a small silica gel pad, followed by removal of thesolvent. The crude product was re-dissolved in 5N NaOH solution in waterand stirred at room temperature for 2 hours. The crude product waspurified on Flashmaster II to afford 250 mg of5-fluoro-2-methylisonicotinic acid.

5-[(2-fluoro-4-iodophenyl)amino]-2-methylisonicotinic acid

5-[(2-fluoro-4-iodophenyl)amino]-2-methylisonicotinic acid wassynthesized according to the general procedure of Method 1 as, outlinedabove, starting with 200 mg (1.29 mmol) of 5-fluoro-2-methylisonicotinicacid, 370 mg (1.55 mmol) of 2-fluoro-4-iodoaniline and two portions oflithium bis(trimethylsilyl)amide (3.35 ml, 3.35 mmol), and (1.55 ml,1.55 mmol). Yield: 30 mg, 6%, LC/MS [5.5 min; 473 (M+1)]

Method for the Synthesis of 2-Aryl-3-Phenylamino-Isonicotinic AcidDerivatives

A typical procedure for the synthesis of2-alkyl-3-phenylamino-isonicotinic acid derivatives:

5-fluoro-2-phenylpyridine

To a solution of 2-bromo-5-fluoropyridine (10.0 g, 56.82 mmol, Aldrich)in tetrahydrofuran (100 ml) was added tetrakis (triphenylphosphine)Pdcomplex and stirred for 10 min. Then, phenylmagnesium bromide (68.2 ml,1.00 M in THF, 68.19 mmol) was added drop-wise at 0° C. The mixture wasstirred overnight. Then the reaction was diluted with EtOAc (600 ml),and filtered. The filtrate was concentrated and purified by flashchromatography by eluting with 2% EtOAc-Hexane to obtain 6.8 g (69%) of5-fluoro-2-phenylpyridine.

5-fluoro-2-phenylisonicotinic acid

To a solution of 5-fluoro-2-phenylpyridine (760.0 mg, 4.39 mmol) intetrahydrofuran (15.0 ml) was added n-butyllithium (2.11 ml, 2.50 M inTHF, 5.27 mmol) at −45° C. The mixture was stirred for 1 h at −45° C.,then poured into THF containing dry ice Stirred for 1 h, then MeOH (2ml) was added. The solution was concentrated, and purified onFlashmaster II to get 560 mg (58%) of 5-fluoro-2-phenylisonicotinicacid.

5-[(2-fluoro-4-iodophenyl)amino]-2-phenyl isonicotinic acid

Lithium bis(trimethylsilyl)amide (2.8 ml, 1.0 M in THF, 2.76 mmol) wasadded to a suspension of 5-fluoro-2-phenylisonicotinic acid (500 mg,2.30 mmol) in THF (10 ml) at −78° C. The dark colored suspension wasstirred for 30 min. In another flask, 2-fluoro-4-iodoaniline (709.30 mg,2.99 mmol, 1.30 eq) was dissolved in (15 ml) THF and cooled to −78° C.To this solution lithium bis(trimethylsilyl)amide (5 ml, 1.00 M, 5.06mmol, 2.20 eq) was added and the mixture was stirred for 1 h. Thereaction mixture became very viscous. To this, the homogeneous solutionof acid-LiHMDS mixture was added via syringe. The mixture was warmed toroom temperature and stirred overnight. Diluted with EtOAc (300 ml),washed with dilute HCl (20 ml), water (20 ml), and then dried andconcentrated. Purified on Flashmaster using 100 g cartridge to obtain565 mg of 5-[(2-fluoro-4-iodophenyl)amino]-2-phenylisonicotinic acid.LC/MS: [8.59 min; 435 (M+1)]

Example 7N-{[(2R)-2,3-dihydroxypropyl]oxy}-3-[(2-fluoro-4-iodophenyl)-amino]isonicotin-amide

A suspension ofN-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide(synthesis described below) (3.0 g, 6.16 mmol) in dichloromethane (20mL) was treated with trifluoroacetic acid (20 mL) and the clear-yellowsolution was stirred at room temp. After stirring for 8 h, the contentswere concentrated to a yellow oil, which was dissolved in ethyl acetate(100 mL) and poured into water (150 mL). The pH of the biphasic mixturewas adjusted between 6 and 7 with 2.0 N aqueous sodium hydroxide and thelayers were separated. The organics were dried over sodium sulfate,concentrated to a yellow oil and placed under high vacuum at 40° C. Theresultant yellow, solid foam weighed 2.39 g (5.34 mmol, 87%) afterdrying for 18 h. LC/MS [5.22 min; 448 (M+1)]

N-{[(2R)-2,3-dihydroxypropyl]oxy}-3-[(2-fluoro-4-iodophenyl)-amino]isonicotin-amidehydrochloride

The diol from the previous entry (2.09 g, 4.67 mmol) was suspended inwater (20 mL) and treated with aqueous 1.0 N HCl (4.7 mL). Completedissolution occurred and the solution was placed on the lyophilizer.After 18 h, the yellow solid weighed 2.23 g (4.61 mmol, 99%). LC/MS[5.22 min; 448 (M+1)]

Example 7aN-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

A mixture of the carboxylic acid Intermediate 1 (3.00 g, 8.38 mmol) andCDI (1.70 g, 10.48 mmol) was suspended in dry DMSO (40 mL) and thecontents were stirred at room temp for 15 h. At that time, thedark-yellow solution was treated with the amine (2.05 g, 13.93 mmol) andthe contents were stirred at room temp for 5 h and then poured intobrine (250 mL) and extracted with ethyl acetate (250 mL). The organicswere washed with brine (2×250 mL), dried over sodium sulfate andconcentrated to a solid (3.06 g, 75%) LC/MS [6.03 min; 488 (M+1)]

3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid

To suspension of 3-fluoroisonicotinic acid (2.00 g, 14.17 mmol, intetrahydrofuran (50 ml) at −78° C. was added lithiumbis(trimethylsilyl)amide (14.3 ml, 17.01 mmol). The dark coloredsuspension was stirred for 15 min. In another flask, to a solution of2-chloro-4-iodoaniline (4.7 g, 18.43 mmol) in THF (50 ml) was addedlithium bis(trimethylsilyl)amide (24.9 ml, 29.77 mmol) at −78° C. underN₂. The resulting green colored solution was stirred for 15 min. To thisgreen colored solution the lithiated acid solution was added. The coldbath was removed, allowed to warm to room temperature, and stirredovernight. The mixture was filtered, and the crude was diluted withEtOAc (400 ml). It was then washed with dilute HCl (25 ml), H₂O (25 ml),and dried. During concentration of the solvent,3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid was separated out asan yellow solid. (1.3 g, 24%)

Example 7b3-[(2-chloro-4-iodophenyl)amino]-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}isonicotinamide

From the previous reaction 3-[(2-chloro-4-iodophenyl)amino]isonicotinic(120.00 mg, 0.32 mmol) acid was suspended in dichloromethane (5 ml).Pyridine (50.68 mg, 0.64 mmol) and N,N-Diisopropylethylamine (82.81 mg,0.64 mmol) (DIEA helps to obtain a homogeneous solution) were added. Tothis mixture was added oxalyl chloride (121.99 mg, 0.96 mmol) andstirred for 1 h at room temperature. The mixture was concentrated, andthe residue was dried under vacuum. The crude acid chloride wasdissolved in DCM (5 ml) and DIEA was added (83 mg, 0.64 mmol,) followedby O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (142 mg,0.96 mmol,). The reaction mixture was stirred for 3 h, it concentrated,and purified on Flashmaster II to get 125 mg of3-[(2-chloro-4-iodophenyl)amino]-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}isonicotinamidein 770% yield.

Example 83-[(2-chloro-4-iodophenyl)amino]-N-{[(2R)-2,3-dihydroxypropyl]oxy}-isonicotinamide

3-[(2-chloro-4-iodophenyl)amino]-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}isonicotinamide(100.00 mg, 0.198 mmol.) from the reaction described above was dissolvedin acetic acid (1 ml) was heated at 90° C. for 2 h. The reaction wasmonitored by HPLC. After completion, acetic acid was removed and thecrude was purified on Flashmaster II to obtain 40 mg (43%) of3-[(2-chloro-4-iodophenyl)amino]-N-{[(2R)-2,3-dihydroxypropyl]oxy}isonicotinamide.LC/MS: [7.97 min; 464, 466 (M+1)]

Example 93-[(2-methyl-4-iodophenyl)amino]-N-{[(2R)-2,3-dihydroxypropyl]oxy}-isonicotinamide

3-[(2-methyl-4-iodophenyl)amino]-N-{[(2R)-2,3-dihydroxypropyl]oxy}isonicotinamidewas synthesized as3-[(2-chloro-4-iodophenyl)amino]-N-{[(2R)-2,3-dihydroxypropyl]oxy}isonicotinamideusing Intermediate 3 instead of intermediate 2. LC/MS: [7.36 min; 464,445 (M+1)]

Example 10 Methyl 3-[(2-chloro-4-iodophenyl)amino]isonicotinate

Carboxylic acid Intermediate 2 (0.200 g, 0.534 mmol) and CDI (0.095 g,0.586 mmol) in dry DMSO (5 mL) was stirred at room temp for 18 h. Theclear-yellow solution was then treated with dry methanol (0.5 mL) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.090 g. 0.591 mmol) and thecontents were warmed to 50° C. After 2 days, the dark-yellow solutionwas poured into water and ethyl acetate. The layers were separated andthe organics were washed with brine dried and concentrated to a yellowsolid (0.207 g, 100%). LC/MS [8.20 min; 389 (M+1)]

Example 11 3-[(2-chloro-4-iodophenyl)amino]isonicotinamide

3-[(2-chloro-4-iodophenyl)amino]isonicotinamide was synthesizedaccording to the procedure for General Method 1, outlined above,starting with 6 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinicacid (intermediate 2) and 12 mmol of. ammonium acetate. LC/MS [8.29 min;374 (M+1)]

3-[(2-chloro-4-iodophenyl)amino]isonicotinamide hydrochloride

The amide form the previous entry (4.5 mmol) was suspended in water (10mL) and treated with aqueous 1.0 N HCl (9 mL). The contents were stirredfor 15 min, cooled to 3° C. and filtered. The yellow-green solid wasdried under high vacuum at 40° C. LC/MS [8.29 min; 374 (free base, M+1)]

Example 12 3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesizedaccording to the procedure for General Method 1, outlined above,starting with 8 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinicacid (intermediate 1) and 16 mmol of. ammonium acetate. LC/MS [7.27 min;358 (M+1)].

3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide hydrochloride

The amide form the previous entry (4 mmol) was suspended in water (12mL) and treated with aqueous 1.0 N HCl (8 mL). The contents were stirredfor 15 min, cooled to 3° C. and filtered. The yellow-green solid wasdried under high vacuum at 40° C. LC/MS [7.26 min; 358 (free base, M+1)]

Example 133-(2-Fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamide

3-(2-Fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.35 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.50 mmol of. 2-morpholin-4-yl-ethylamine LC/MS [1.74 min; 471 (M+1)].

Example 143-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxypropyl)-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxypropyl)isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.45 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.62 mmol of 2-amino-isopropanol. LC/MS [5.11 min; 416 (M+1)]

Example 153-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide

3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.39 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.50 mmol of ethanolamine. LC/MS [3.42 min; 402 (M+1)]

Example 163-(2-Fluoro-4-iodo-phenylamino)-N-(2-methoxy-ethyl)-isonicotinamide

3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.45 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.60 mmol of 2-methoxy-ethylamine. LC/MS [3.42 min; 402 (M+1)]

Example 17[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-morpholin-4-yl-methanone

3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-morpholin-4-yl-methanonewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.36 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.47 mmol of morpholine. LC/MS [7.67 min; 428 (M+1)].

Example 18 N-ethyl-3-[(2-fluoro-4-iodophenyl)amino] isonicotinamide

N-ethyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesizedaccording to the procedure for General Method 1, outlined above,starting with 0.34 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinicacid (intermediate 1) and 0.48 mmol of monoethylamine. LC/MS [5.96 min;386 (M+1)]

Example 193-[(2-fluoro-4-iodophenyl)amino]-N-piperidin-1-ylisonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-piperidin-1-ylisonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.30 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.47 mmol of piperidin-1-ylamine LC/MS [8.81 min; 441 (M+1)]

Example 203-[(2-fluoro-4-iodophenyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.40 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.60 mmol of 3-imidazol-1-yl-propylamine. LC/MS [4.82 min; 466 (M+1)]

Example 21 N-benzyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

N-benzyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesizedaccording to the procedure for General Method 1, outlined above,starting with 0.3 mmol 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid(intermediate 1) and 0.45 mmol of benzylamine. LC/MS [7.55 min; 448(M+1)]

Example 22 3-[(2-chloro-4-iodophenyl)amino]-N-methylisonicotinamide

3-[(2-chloro-4-iodophenyl)amino]-N-methylisonicotinamide was synthesizedaccording to the procedure for General Method 1, outlined above,starting with 0.32 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinicacid (intermediate 2) and 0.43 mmol of monomethylamine LC/MS [9.23 min;389 (M+1)]

Example 23 3-[(2-chloro-4-iodophenyl)amino]-N-dimethylisonicotinamide

3-[(2-chloro-4-iodophenyl)amino]-N-dimethylisonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.30 mmol of3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and0.40 mmol of dimethylamine LC/MS [8.38 min; 402.7 (M+1)]

Example 243-[(2-fluoro-4-iodophenyl)amino]-N-(2-methoxyethyl)-N-methyl-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(2-methoxyethyl)-N-methylisonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.42 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.57 mmol of (2-methoxy-ethyl)-dimethyl-amine LC/MS [7.84 min; 430(M+1)]

Example 253-[(2-fluoro-4-iodophenyl)amino]-N-morpholin-4-ylisonicotin-amide

3-[(2-fluoro-4-iodophenyl)amino]-N-morpholin-4-ylisonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.5 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.81 mmol of morpholin-4-ylamine LC/MS [8.25 min; 443 (M+1)]

Example 263-[(2-fluoro-4-iodophenyl)amino]-N-(2-phenoxyethyl)-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(2-phenoxyethyl)isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.32 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.45 mmol of 2-phenoxyethylamine. LC/MS [10.10 min; 478 (M+1)]

Example 273-[(2-fluoro-4-iodophenyl)amino]-N-[2-(2-methoxyphenyl)-ethyl]isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-[2-(2-methoxyphenyl)ethyl]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.54 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.81 mmol of 2-(2-methoxy-phenyl)-ethylamine. LC/MS [10.19 min; 492(M+1)]

Example 28N′-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-1H-indazole-3-carbohydrazide

N′-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-1H-indazole-3-carbohydrazidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.32 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.47 mmol of 1H-indazole-3-carboxylic acid hydrazide. LC/MS [9.14 min;517 (M+1)]

Example 29N-[2-(3-chlorophenyl)ethyl]-3-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide

N-[2-(3-chlorophenyl)ethyl]-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.5 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.75 mmol of 2-(3-chlorophenyl)ethylamine. LC/MS [10.47 min; 496 (M+1)]

Example 303-[(2-fluoro-4-iodophenyl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.6 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.85 mmol of 1-(3-amino-propyl)-pyrrolidin-2-one LC/MS [8.70 min; 483(M+1)]

Example 31 2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide

2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesizedaccording to the procedure for General Method 1, outlined above,starting with 0.2 mmol of2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid and 0.5 mmolof ammonium acetate. LC/MS [8.61 min; 392 (M+1)].

Example 323-[(2-fluoro-4-iodophenyl)amino]-N′-phenylisonicotinohydrazide

3-[(2-fluoro-4-iodophenyl)amino]-N′-phenylisonicotinohydrazide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.45 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.7 mmol of phenylhydrazine. LC/MS [9.52 min; 449 (M+1)]

Example 333-[(2-fluoro-4-iodophenyl)amino]-N-(2-piperidin-1-ylethyl)-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(2-piperidin-1-ylethyl)isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 2.5 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and4.0 mmol of 2-piperidin-1-ylethylamine. LC/MS [5.40 min; 469 (M+1)]

Example 34tert-butyl(1-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-piperidin-4-yl)carbamate

tert-butyl(1-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}piperidin-4-yl)carbamatewas synthesized according to the procedure for General Method 1,outlined above, starting with 2.4 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and4.0 mmol of piperidin-4-yl-carbamic acid tert-butyl ester. LC/MS [9.47min; 541 (M+1)]

Example 353-[(2-fluoro-4-iodophenyl)amino]-N-(3-morpholin-4-ylpropyl)-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(3-morpholin-4-ylpropyl)isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 1.0 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and1.6 mmol of 3-morpholin-4-yl-propylamine. LC/MS [4.66 min; 485 (M+1)]

Example 363-(2-Chloro-4-iodo-phenylamino)-N-(5-hydroxy-pentyl)-isonicotinamide

3-(2-Chloro-4-iodo-phenylamino)-N-(5-hydroxy-pentyl)-isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.30 mmol of3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and0.40 mmol of 5-amino-pentan-1-ol. LC/MS [9.33 min; 461 (M+1)]

Example 373-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethylmethyl-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethylmethylisonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.4 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.6 mmol of 2-methylamino-ethanol. LC/MS [6.47 min; 416 (M+1)]

Example 382-Chloro-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide

2-Chloro-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.2 mmol of2-chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid and 0.3 mmolof O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-hydroxylamine LC/MS[9.19 min; 522 (M+1)].

Example 393-[(2-fluoro-4-iodophenyl)amino]-N-(4-hydroxybutyl)-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(4-hydroxybutyl)isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.5 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.63 mmol of 4-hydroxy-butylamine. LC/MS [8.42 min; 430 (M+1)]

Example 403-[(2-fluoro-4-iodophenyl)amino]-N-(pyridin-2-ylmethyl)-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(pyridin-2-ylmethyl)isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.46 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.78 mmol of pyridine-2-methylamine. LC/MS [8.33 min; 449 (M+1)]

Example 413-[(2-fluoro-4-iodophenyl)amino]-N-[(2S)-2-hydroxypropyl]-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-[(2S)-2-hydroxypropyl]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.3 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.4 mmol of 2-(R)-hydroxypropylamine. LC/MS [8.40 min; 416 (M+1)]

Example 42 N-azepan-1-yl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

N-azepan-1-yl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.45 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and6.2 mmol of azepan-1-ylamine. LC/MS [8.99 min; 455 (M+1)]

Example 432-Chloro-N-[(2R)-2,3-dihydroxy-propoxy]-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide

Deprotection of2-Chloro-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamidewith 50:50 mixture of TFA/dichloromethane at room temperature for 30minutes afforded the desired product. Purification by reverse phaseLC/MS [7.94 min; 482 (M+1)].

Example 444-[(4-aminopiperidin-1-yl)carbonyl]-N-(2-fluoro-4-iodophenyl)pyridin-3-aminehydrochloride

4-[(4-aminopiperidin-1-yl)carbonyl]-N-(2-fluoro-4-iodophenyl)pyridin-3-aminewas synthesized fromtert-butyl(1-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}piperidin-4-yl)carbamate(described below) by deprotection of the Boc group with TFA/DCM: 0.33mmol oftert-butyl(1-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}piperidin-4-yl)carbamatewas dissolved in 4 ml of 50:50 mixture of TFA/dichloromethane. After 2hours of stirring at room temperature the volatiles were stripped andthe residue was re-dissolved in 2 ml of methanol. 1.0N HCl indiethylether was added and the product precipitated. LC/MS [2.01 min;441 (free base, M+1)]

Example 45 tert-butyl2-{3-[(2-fluoro-4-iodophenyl)amino]-isonicotinoyl}hydrazine-carboxylate

tert-butyl2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}hydrazine-carboxylatewas synthesized according to the procedure for General Method 1,outlined above, starting with 3 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 5mmol of hydrazinecarboxylic acid tert-butylester. LC/MS [9.37 min; 473(M+1)]

Example 464-[({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-amino)methyl]benzoicacid

4-[({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-amino)methyl]benzoicacid was synthesized according to the procedure for General Method 1,outlined above, starting with 0.3 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.45 mmol of 4-aminomethylbenzoic acid. LC/MS [9.25 min; 492 (M+1)]

Example 47 N-cyclopropyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

N-cyclopropyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.2 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.23 mmol of cyclopropylamine. LC/MS [8.78 min; 398 (M+1)]

Example 483-[(2-fluoro-4-iodophenyl)amino]-N-[(2R)-2-hydroxypropyl]-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-[(2R)-2-hydroxypropyl]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 2 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 3mmol of 2-(R)-hydroxypropylamineLC/MS [8.33 min; 416 (M+1)]

Example 493-[(2-fluoro-4-iodophenyl)amino]-N′-pyridin-2-ylisonicotino-hydrazide

3-[(2-fluoro-4-iodophenyl)amino]-N′-pyridin-2-yl isonicotinohydrazidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.5 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.8 mmol of pyridin-2-yl-hydrazine. LC/MS [6.90 min; 450 (M+1)]

Example 503-[(2-fluoro-4-iodophenyl)amino]-N′-[4-(trifluoromethyl)pyrimidin-2-yl]isonicotinohydrazide

3-[(2-fluoro-4-iodophenyl)amino]-N′-[4-(trifluoromethyl)pyrimidin-2-yl]isonicotinohydrazide was synthesized according tothe procedure for General Method 1, outlined above, starting with 0.4mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid(intermediate 1) and 0.6 mmol of4-trifluoromethyl-pyrimidin-2-yl)-hydrazine. LC/MS [9.38 min; 519 (M+1)]

Example 51 3-[(2-fluoro-4-iodophenyl)amino]isonicotinohydrazide

3-[(2-fluoro-4-iodophenyl)amino]isonicotinohydrazide hydrochloride wassynthesized from tert-butyl2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}hydrazine-carboxylate(described earlier) by deprotection of the Boc group under acidicconditions (50:50 TFA/DCM). LC/MS [7.11 min; 373 (free base, M+1)]

Example 525-[(2-fluoro-4-iodophenyl)amino]-2-(4-methoxyphenyl)isonicotinic acid

5-[(2-fluoro-4-iodophenyl)amino]-2-(4-methoxyphenyl)isonicotinic acidwas synthesized according to the General method 5, outlined above. First5-Fluoro-2-(4-methoxyphenyl)pyridine was synthesized starting with 1.0 g(5.68 mmol) of 2-bromo-5-fluoropyridine and p-methoxy phenylmagnesiumbromide (13.7 ml, 0.5 M in THF, 6.82 mmol) in the presence of 0.66 g(0.57 mmol) of tetrakis (triphenyl phosphine)Pd complex. Yield: 766 mg,66%. Then 5-fluoro-2-(4-methoxyphenyl)isonicotinic acid was synthesizedfrom 765 mg (3.76 mmol) of 5-fluoro-2-(4-methoxyphenyl)pyridine,butyllithium (1.8 ml, 2.50 M in THF, 4.52 mmol) and dry ice. Yield: 450mg, 48%.5-[(2-fluoro-4-iodophenyl)amino]-2-(4-methoxyphenyl)isonicotinic acidwas then synthesized with 2.37 mmol of 2-fluoro-4-iodoaniline and by1.82 mmol of 5-fluoro-2-(4-methoxyphenyl)isonicotinic acid as describedin General Method 5. LC/MS [9.52 min, 465 (M+1)]

Example 53N-(cyclopropylmethyl)-3-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide

N-(cyclopropylmethyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.2 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.23 mmol of cyclopropylmethylamine. LC/MS [9.79 min; 412 (M+1)]

Example 543-(2-Chloro-4-ethynyl-phenylamino)-N-(2,3-dihydroxy-propoxy)-isonicotinamide

0.43 mmol of3-[(2-chloro-4-iodophenyl)amino]-N-{[(2R)-2,3-dihydroxypropyl]oxy}isonicotinamide(synthesis described above), 0.02 mmol ofdichlorobis(triphenylphosphine)palladium(II), and 0.03 mmol of copper(I) iodide were dissolved and DMF and TEA. 0.93 mmol oftrimethylsilylacetylene was added to the stirring solution and theresultant orange mixture was vigorously stirred for 18 h at ambienttemperature. The solvent was then removed under reduced pressure and theresidue was diluted with EtOAc, washed with water (2×) and saturatedbrine (2×). The organics were dried over Na₂SO₄, filtered, and thenconcentrated under reduced pressure to give a brown solid, which wasthen dissolved in methanol. 3.10 mmol of CsF was added and the mixturewas stirred at ambient temperature. After stirring for 16 h, thesolution was concentrated, taken up in EtOAc, and then the organic phasewas washed with water, brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was subjected to columnchromatography (Flashmaster) on silica gel using EtOAc/MeOH (0-100%) toafford the desired product LC/MS [5.29 min; 362 (M+1)]

Example 553-[(2-fluoro-4-iodophenyl)amino]-N′-(3-methoxybenzoyl)-isonicotinohydrazide

3-[(2-fluoro-4-iodophenyl)amino]-N′-(3-methoxybenzoyl)isonicotinohydrazidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.4 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.55 mmol of 3-methoxy-benzohydrazide. LC/MS [9.23 min; 507 (M+1)]

Example 56N′-(7-chloroquinolin-4-yl)-3-[(2-fluoro-4-iodophenyl)amino]-isonicotino-hydrazide

N′-(7-chloroquinolin-4-yl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotino-hydrazidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.33 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.50 mmol of 7-chloroquinolin-4-yl-hydrazine.LC/MS [7.69 min; 534 (M+1)]

Example 572-[4-(dimethylamino)phenyl]-5-[(2-fluoro-4-iodophenyl)amino]-isonicotinicacid

2-[4-(dimethylamino)phenyl]-5-[(2-fluoro-4-iodophenyl)amino]isonicotinicacid was synthesized according to the General Method 5, outlined above.First 4-(5-fluoropyridin-2-yl)-N,N-dimethylaniline was synthesizedstarting with 5.68 mmol of 2-bromo-5-fluoropyridine and4-(N,N-dimethyl)anilinemagnesium bromide (6.82 mmol) in the presence of0.66 g (0.57 mmol) of tetrakis (triphenylphosphine)Pd complex. Yield:650 mg, 59%. Then 2-[4-(dimethylamino)phenyl]-5-fluoroisonicotinic acidwas synthesized from 2.66 mmol of4-(5-fluoropyridin-2-yl)-N,N-dimethylaniline, butyllithium (17.3 mmol)and dry ice. Yield: 460 mg, 66%.5-[(2-fluoro-4-iodophenyl)amino]-2-(4-methoxyphenyl)isonicotinic acidwas then synthesized with 1.25 mmol of 2-fluoro-4-iodoaniline and by0.96 mmol of 2-[4-(dimethylamino)phenyl]-5-fluoroisonicotinic acid asdescribed in General Method 5. LC/MS: [8.86 min, 478 (M+1)]

Example 58 N-cyclobutyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

N-(cyclobutyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.34 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.42 mmol of cyclobutylamine.LC/MS [9.86 min; 412 (M+1)]

Example 59N-(2,3-dihydro-1H-inden-1-yl)-3-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide

N-(2,3-dihydro-1H-inden-1-yl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.43 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.57 mmol of indanylamine. LC/MS [10.69 min; 474 (M+1)]

Example 60 N-cyclopentyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

N-cyclopentyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.45 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.57 mmol of cyclopentylamine. LC/MS [9.55 min; 426 (M+1)]

Example 61 N-cyclohexyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

N-cyclohexyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.33 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.42 mmol of cyclohexylamine. LC/MS [10.52 min; 440 (M+1)]

Example 62N-(1,2-dimethylpropyl)-3-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide

N-(1,2-dimethylpropyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.4 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.6 mmol of 2,3,dimethyl butylamine LC/MS [10.32 min; 428 (M+1)]

Example 63N-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

N-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized as its isomerN-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamideLC/MS.[8.94 min; 488 (M+1)]

Example 64N-(2-Acetylamino-ethyl)-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide

N-(2-Acetylamino-ethyl)-3-(2-chloro-4-iodo-phenylamino)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.32 mmol of3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and0.44 mmol N-(2-amino-ethyl)-acetamideLC/MS [8.38 min; 4.59 (M+1)]

Example 65 3-(2-Chloro-4-iodo-phenylamino)-pyridine-4-carbonyl]-carbamicacid tert-butyl ester

3-(2-Chloro-4-iodo-phenylamino)-pyridine-4-carbonyl]-carbamic acidtert-butyl ester was synthesized according to the procedure for GeneralMethod 1, outlined above, starting with 0.6 mmol of3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and0.8 mmol of carbamic acid tert-butyl ester. LC/MS [9.69 min; 445.8(M+1)]

Example 66 3-[(2-fluoro-4-iodophenyl)amino]-N-hydroxyisonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-hydroxyisonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.31 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.6 mmol of hydroxylamine. LC/MS [7.37 min; 374 (M+1)]

Example 67 3-(4-iodo-phenylamino)-isonicotinamide

3-(4-iodo-phenylamino)-isonicotinamide was synthesized according to theprocedure for General Method 1, outlined above, starting with 0.2 mmolof 3-(4-iodophenyl)amino-isonicotinic acid and 0.4 mmol of ammoniumacetate. LC/MS [5.03 min; 340 (M+1)]

Example 68 2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide

The synthesis of 2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamidewas described under General Method 3.

Example 692-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)-amino]isonicotinamidewas synthesized as described in General Method 3: to a solution of2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (145.0 mg,0.33 mmol) in DMF (1.5 ml) was added 1,1′-carbonylbis(1H-imidazole) (60mg, 0.36 mmol). The reaction mixture was stirred at room temperatureunder argon for 6 hrs. Then,O-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]hydroxylamine (125 mg 0.83mmol) was added, and stirred overnight. The reaction mixture was pouredinto water (10 ml). Extracted with EtOAc(3×15 ml), the combined organiclayer was washed with brine (2×15 ml), and dried over MgSO₄. The solventwas evaporated, and the residue was purified on silica gel column(Hex:EtOAc=3:1) to obtain 104 mg (55%) of2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide.LC/MS:10.43 min, 566, 568.

Example 702-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-hydroxy-propyl)-isonicotinamide

2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-hydroxy-propyl)-isonicotinamidewas synthesized according to General method 3, starting with 145 mg(0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acidand 62 mg (0.82 mmol) of 3-Amino-propan-1-ol. LC/MS: [9.15 min, 494,496]

Example 712-Bromo-N-(2,4-dihydroxy-butoxy)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide

2-Bromo-N-(2,4-dihydroxy-butoxy)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamidewas synthesized as described in General method 3: To a solution of2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide(100.0 mg 0.18 mmol) in dichloromethane (1 ml) was added trifluoroaceticacid (1 ml) at RT. The reaction mixture was stirred at RT for 30 min,and monitored by TLC (Hex:EtOAc=1:1 and contain TEA). Upon completion,the volatiles were evaporated, and the residue was dissolved indichloromethane, washed with 5% aq. NaHCO₃ to get a precipitate. Theresidue was filtered, washed with water, and dried to get 53 mg (56%) of2-Bromo-N-(2,4-dihydroxy-butoxy)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide.LC/MS: [8.76 min, 541 (M+1)]

Example 722-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-imidazol-1-yl-propyl)-isonicotinamide

2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-imidazol-1-yl-propyl)-isonicotinamidewas synthesized according to the General Method 3, starting with 145 mg(0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acidand 103 mg (0.83 mmol) of 3-Imidazol-1-yl-propylamine. Yield: 55 mg,30%, LC/MS: [7.31 min, 545 (M+1)]

Example 73 3-(4-iodo-phenylamino)-isonicotinic acid

3-(4-iodo-phenylamino)-isonicotinic acid was synthesized according tothe procedure for General Method 1 and as Intermediate 1 by reacting 1.4mmol of 4-iodoaniline with 2.8 mmol of 2-fluoro-isonicotinic acid LC/MS[6.29 min; 341(M+1)].

Example 742-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide

2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamidewas synthesized according to General Method 3, starting with 145 mg(0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid51 mg (0.83 mmol) of 2-amino-ethanol. LC/MS: [8.98 min, 480, 482]

Example 75N-{[(2S)-2,3-dihydroxypropyl]oxy}-3-[(2-fluoro-4-iodophenyl)-amino]isonicotin-amide

N-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide(0.162 g, 0.332 mmol) was suspended in dichloromethane (4 mL) and thentreated with trifluoroacetic acid (4 mL). The dark-yellow solution wasstirred at room temp for 24 h, concentrated, re-dissolved in methanol(10 mL) and concentrated again. The residue was then placed in ethylacetate (15 mL) and brine (20 mL) and the pH was adjusted between 6 and7 with aqueous 2 N NaOH. The layers were separated and the organics werewashed with brine (25 mL), concentrated to a yellow oil and placed underhigh vacuum for 3 h to afford the diol as a yellow semi-solid (0.118 g,80%). LC/MS [7.11 min; 448 (M+1)]

Example 76 N-ethoxy-3-(4-iodo-phenylamino)-isonicotinamide

N-ethoxy-3-(4-iodo-phenylamino)-isonicotinamide was synthesizedaccording to the procedure for General Method 1, outlined above,starting with 0.30 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinicacid (intermediate 2) and 0.40 mmol of O-ethyl-hydroxylamine LC/MS [9.14min; 418 (M+1)]

Example 77 N-allyloxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide

N-allyloxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.20 mmol of3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and0.36 mmol of O-allyl-hydroxylamine. LC/MS [9.30 min; 430 (M+1)]

Example 78 N-isopropoxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide

N-isopropoxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.30 mmol of3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and0.42 mmol of O-Isobutyl-hydroxylamine. LC/MS [10.06 min; 446 (M+1)]

Example 79N-(3-chloropropyl)-3-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide

N-(3-chloropropyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 1 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and1.3 mmol of 3-chloropropylamine. LC/MS [9.24 min; 434 (M+1)]

Example 80 N-methoxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide

N-methoxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.30 mmol of3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and0.42 mmol of O-methyl-hydroxylamine. LC/MS [8.75 min; 404 (M+1)]

Example 81 N-Benzyloxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide

N-Benzyloxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.25 mmol of3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and0.36 mmol of O-methyl-hydroxylamine. LC/MS [10.0]min; 480 (M+1)]

Example 82N-bicyclo[2.2.1]hept-2-yl-3-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide

N-bicyclo[2.2.1]hept-2-yl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.31 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.45 mmol of bicyclo[2.2.1]hept-2-ylamine. LC/MS [10.01 min; 452 (M+1)]

Example 833-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyphenoxypropyl)-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyphenoxypropyl)isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.34 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.45 mmol of 2-hydroxyphenoxypropylamine. LC/MS [9.53 min; 508 (M+1)]

Example 843-[(2-fluoro-4-iodophenyl)amino]-N-(tetrahydro-2H-pyran-2-yloxy)-isonicotin-amide

3-[(2-fluoro-4-iodophenyl)amino]-N-(tetrahydro-2H-pyran-2-yloxy)isonicotin-amidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.4 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.52 mmol of O-(tetrahydro-pyran-2-yl)-hydroxylamine. LC/MS [9.07 min;458 (M+1)]

Example 853-[(2-fluoro-4-iodophenyl)amino]-N-[2-(4-methylphenyl)-ethyl]isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-[2-(4-methylphenyl)ethyl]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.54 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.62 mmol of 2-(4-methylphenyl)ethylamine. LC/MS [10.25 min; 476 (M+1)]

Example 86N-(1-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}piperidin-4-yl)-2-(4-methylphenyl)acetamide

A mixture of p-tolyl acetic acid (0.027 g, 0.180 mmol) and CDI (0.036 g,0.222 mmol) in dry DMSO (2 mL) was heated to 50° C. for 2 h prior toaddition of4-[(4-aminopiperidin-1-yl)carbonyl]-N-(2-fluoro-4-iodophenyl)pyridin-3-aminehydrochloride (described above) (0.052 g, 0.109 mmol). The contents werethen stirred at room temp. After 6 h, HPLC indicated near-completereaction. The contents were poured into water (30 mL) and extracted withethyl acetate (30 mL). The organics were washed with brine (2×30 mL),dried over sodium sulfate and concentrated to a yellow oil. The oil wasfurther dried under high vacuum for 2 h at 40° C. to provide the desiredproduct as a yellow semi-solid (0.068 g, 0.119 mmol, 66%). LC/MS [8.92min; 573 (M+1)]

Example 872-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-methoxy-ethyl)-isonicotinamide

2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-methoxy-ethyl)-isonicotinamidewas synthesized according to the General method 3, starting with 145 mg(0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acidand 51 mg (0.83 mmol) of 2-amino-ethanol. Yield: 88 mg, 55%, LC/MS:[9.55 min; m/z: 495 (M+1)]

Example 882-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamide

2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamidewas synthesized according to the General Method 3 starting with 145 mg(0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acidand 108 mg (0.83 mmol) of 2-morpholin-4-yl-ethylamine. Yield: 95 mg,52%. LC/MS: [7.08 min, 550, 552 (M+1)]

Example 89N-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-(2-fluoro-4-iodo-phenylamino)-1-oxy-isonicotinamide

N-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-(2-fluoro-4-iodo-phenylamino)-1-oxy-isonicotinamidewas synthesized as described in General Method 2: to a solution of3-(2-Fluoro-4-iodo-phenylamino)-1-oxy-isonicotinic acid (110 mg, 0.29mmol) in DMF (1.2 ml) was added 1,1′-carbonylbis(1H-imidazole) (52.45mg, 0.32 mmol). The reaction mixture was stirred at RT under argon for 6hrs. Then, O-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]hydroxylamine (109mg 0.74 mmol) was added, and the mixture stirred overnight. Then, it waspoured into water (10 ml), extracted with EtOAc (3×15 ml), and thecombined organic layers were washed with brine (2×15 ml), and dried overMgSO₄. The solvent was evaporated, and the residue was purified onsilica gel column to obtain 75 mg (51%) ofN-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-(2-fluoro-4-iodo-phenylamino)-1-oxy-isonicotinamide.LC/MS: [8.54 min, 504 (M+1)]

Example 903-[(2-fluoro-4-iodophenyl)amino]-N′-(3-methylphenyl)isonicotino-hydrazide

3-[(2-fluoro-4-iodophenyl)amino]-N′-(3-methylphenyl)isonicotinohydrazide:was synthesized according to the procedure for General Method 1,outlined above, starting with 0.44 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.63 mmol of 3-methyl-phenylhydrazine. LC/MS [6.05 min; 463 (M+1)]

Example 91 N-(benzyloxy)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide

N-(benzyloxy)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.5 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.72 mmol of O-benzyl-hydroxylamine. LC/MS [9.50 min; 464 (M+1)]

Example 92[({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}amino)oxy]acetic acid

[({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}amino)oxy]acetic acidwas synthesized according to the procedure for General Method 1,outlined above, starting with 0.3 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.51 mmol of aminoxy-acetic acid. LC/MS [5.21 min; 432 (M+1)]

Example 93N-(2,4-difluorobenzyl)-3-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide

N-(2,4-difluorobenzyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.33 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.49 mmol of 2,4-difluorobenzylamine. LC/MS [6.28 min; 484 (M+1)]

Example 943-[(2-fluoro-4-iodophenyl)amino]-N-(3-iodobenzyl)isonicotin-amide

3-[(2-fluoro-4-iodophenyl)amino]-N-(3-iodobenzyl)isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.23 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.43 mmol of 3-iodobenzylamine. LC/MS [6.37 min; 574 (M+1)]

Example 95 3-(2-Fluoro-4-iodo-phenylamino)-2-methyl-isonicotinic acid

3-(2-Fluoro-4-iodo-phenylamino)-2-methyl-isonicotinic acid wassynthesized according to the procedure for General Method 1 and asIntermediate 1 by reacting 2 mmol of 2-fluoro-4-iodoaniline with 3.4mmol of 2-fluoro-3-methyl-isonicotinic acid LC/MS [4.63 min; 373 (M+1)].

Example 96N-{[(2R)-2,3-dihydroxypropyl]oxy}-3-(4-iodophenylamino)-isonicotinamide

N-{[(2R)-2,3-dihydroxypropyl]oxy}-3-(4-iodophenylamino)-isonicotinamide3-(4-iodo-phenylamino)-isonicotinamide was synthesized in the samemanner asN-{[(2R)-2,3-dihydroxypropyl]oxy}-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide(described above). LC/MS [7.17 min; 430 (M+1)]

Example 97 3-(2-Fluoro-4-iodo-phenylamino)-1-oxy-isonicotinamide

The synthesis of 3-(2-Fluoro-4-iodo-phenylamino)-1-oxy-isonicotinamidewas described under General Method 2.

Example 98N-(2,2-diethoxyethyl)-3-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide

N-(2,2-diethoxyethyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.33 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.5 mmol of 2,2-diethoxy-ethylamine. LC/MS [5.51 min; 474 (M+1)]

Example 993-[(2-fluoro-4-iodophenyl)amino]-N′-(4-methylphenyl)isonicotino-hydrazide

3-[(2-fluoro-4-iodophenyl)amino]-N′-(4-methylphenyl)isonicotinohydrazidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.4 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.6 mmol of 4-methyl-phenylhydrazine. LC/MS [5.07 min; 463 (M+1)]

Example 100 3-(2-Fluoro-4-iodo-phenylamino)-2-methyl-isonicotinamide

3-(2-Fluoro-4-iodo-phenylamino)-2-methyl-isonicotinamide was synthesizedaccording to the procedure for General Method 1, outlined above,starting with 0.2 mmol of3-[(2-fluoro-4-iodophenyl)amino]-2-methyl-isonicotinic acid and 0.4 mmolof ammonium acetate. LC/MS [1.85 min; 372 (M+1)].

Example 101N′-[3,5-bis(trifluoromethyl)phenyl]-3-[(2-fluoroiodophenyl)amino]-isonicotino-hydrazide

N′-[3,5-bis(trifluoromethyl)phenyl]-3-[(2-fluoroiodophenyl)amino]isonicotino-hydrazidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.37 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.53 mmol of 3,5-ditrifluoromethylbenzylhydrazine. LC/MS [6.47 min; 585(M+1)]

Example 1024-[2-({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-amino)ethyl]benzoicacid

4-[2-({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}amino)ethyl]benzoicacid was synthesized according to the procedure for General Method 1,outlined above, starting with 0.66 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.83 mmol of 4(2-ethylamine)benzoic acid. LC/MS [6.10 min; 506 (M+1)]

Example 1033-[(2-fluoro-4-iodophenyl)amino]-N-[(pentafluorobenzyl)oxy]-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-[(pentafluorobenzyl)oxy]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.32 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.43 mmol of O-pentafluorophenylmethyl-hydroxylamine. LC/MS [6.50 min;554 (M+1)]

Example 1043-[(2-fluoro-4-iodophenyl)amino]-N-(3-methoxyphenyl)-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(3-methoxyphenyl)isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.31 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.46 mmol of 3-methoxyaniline. LC/MS [6.40 min; 464 (M+1)]

Example 1053-[(2-fluoro-4-iodophenyl)amino]-N-[3-fluoro-5-(trifluoromethyl)-benzyl]isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-[3-fluoro-5-(trifluoromethyl)benzyl]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.25 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.37 mmol of 3-fluoro-5-trifluoromethyl-benzylamine. LC/MS [6.51 min;534 (M+1)]

Example 1063-[(2-fluoro-4-iodophenyl)amino]-N-(3-hydroxybenzyl)-isonicotinamide

3-[(2-fluoro-4-iodophenyl)amino]-N-(3-hydroxybenzyl)isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.22 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.35 mmol of 3-hydroxybenzylamine. LC/MS [6.01 min; 464 (M+1)]

Example 107N-(4,4-diethoxybutyl)-3-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide

N-(2,2-diethoxybutyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.30 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.45 mmol of 2,2-dibutyloxy-ethylamine. LC/MS [6.33 min; 502 (M+1)]

Example 108N-(4-Fluoro-benzyl)-3-(2-fluoro-4-iodo-phenylamino)-iso-nicotinamide

N-(4-Fluoro-benzyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide wassynthesized according to the procedure for General Method 1, outlinedabove, starting with 0.25 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.33 mmol of 4-fluoro-benzylamine. LC/MS [6.99 min; 466 (M+1)]

Example 1093-(2-Fluoro-4-iodo-phenylamino)-N-(2,2,2-trifluoro-ethyl)-isonicotinamide

3-(2-Fluoro-4-iodo-phenylamino)-N-(2,2,2-trifluoro-ethyl)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.30 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.45 mmol of 2,2,2-trifluoro-ethylamine. LC/MS [6.73 min; 440 (M+1)]

Example 1103-(2-Fluoro-4-iodo-phenylamino)-N-(1-hydroxymethyl-cyclo-pentyl)-isonicotinamide

3-(2-Fluoro-4-iodo-phenylamino)-N-(1-hydroxymethyl-cyclopentyl)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.25 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.42 mmol of 1-amino-cyclopentyl)-methanol. LC/MS [6.04 min; 456 (M+1)].

Example 111 5-[(2-fluoro-4-iodophenyl)amino]-2-methylisonicotinic acid

The synthesis of 5-[(2-fluoro-4-iodophenyl)amino]-2-methylisonicotinicacid is described under General Method 4.

Example 112N-(1-(S)-Carbamoyl-2-hydroxy-ethyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide

N-(1-(S)-Carbamoyl-2-hydroxy-ethyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.30 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.45 mmol of L-serinamide. LC/MS [5.09 min; 445 (M+1)]

Example 1133-(2-Fluoro-4-iodo-phenylamino)-N-(trans-2-hydroxy-cyclohexyl)-isonicotinamide

3-(2-Fluoro-4-iodo-phenylamino)-N-(trans-2-hydroxy-cyclohexyl)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.27 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.40 mmol of trans-2-aminocyclohexanol. LC/MS [6.40 (10 min) min; 640(M+1)]

Example 114N-(1,1-Bis-hydroxymethyl-propyl)-3-(2-fluoro-4-iodo-phenyl-amino)-isonicotin-amide

N-(1,1-Bis-hydroxymethyl-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.33 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.47 mmol of 2-amino-2-ethyl-propane-1,3-diol. LC/MS [5.93 min; 460(M+1)]

Example 115N-(2,3-dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide

N-(2,3-dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.56 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.84 mmol of 2-amino-2-ethyl-propane-1,3-diol. LC/MS [5.41 min; 432(M+1)]

Example 1163-(2-Fluoro-4-iodo-phenylamino)-N-(3-piperazin-1-yl-propyl)-isonicotinamide

3-(2-Fluoro-4-iodo-phenylamino)-N-(3-piperazin-1-yl-propyl)-isonicotinamidewas synthesized according to the procedure for General Method 1,outlined above, starting with 0.32 mmol of3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and0.47 mmol of. 2-piperazin-1-yl-ethylamine. LC/MS [5.02 min; 484 (M+1)].

Example 117 2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid

2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid wassynthesized as outlined in General Method 1 and according to theprocedure for the synthesis of intermediate 1 by reacting 4 mmol of2-methyl-4-iodoaniline with 6 mmol 2-fluoro-3-chloro-isonicotinic acid.LC/MS [10.25 min; 390.9 (M−1)-ESI-].

Example 118 3-(4-Methoxy-phenylamino)-isonicotinic acid

3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and p-anisidine (44 mg,0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78°C. LiHMDS (1M in THF, 1.24 ml) was added and the mixture was allowed towarm to room temperature over night. Hydrochloric acid (1M in methanol,5 ml) was added and the volatiles were removed in vacuo. The crudematerial was purified by preparative RP chromatography to give 11 mg (45μmol; 13% yield) of pure desired product. LC-MS (method V): rt=1.82 min;m/z [M+H]⁺ 245.

Example 119 3-(4-Trifluoromethylsulfanyl-phenylamino)-isonicotinic acid

3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and4-(trifluoromethylthio)aniline (68.5 mg, 0.354 mmol) was added to 2 mldry THF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24ml) was added and the mixture was allowed to warm to room temperatureover night. Hydrochloric acid (1M in methanol, 5 ml) was added and thevolatiles were removed in vacuo. The crude material was purified bypreparative HPLC to give 11.4 mg (45 μmol; 10% yield) of pure desiredproduct. LC-MS (method V): rt=3.09 min; m/z [M+H]⁺ 315.

Example 120 3-(4-Trifluorornethoxy-phenylamino)-isonicotinic acid

3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and4-(trifluoromethoxy)aniline (62.8 mg, 0.354 mmol) was added to 2 ml dryTHF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24 ml)was added and the mixture was allowed to warm to room temperature overnight. Hydrochloric acid (1M in methanol, 5 ml) was added and thevolatiles were removed in vacuo. The crude material was purified bypreparative HPLC to give 9.5 mg (32 μmol; 9% yield) of pure desiredproduct. LC-MS (method V): rt=2.69 min; m/z [M+H]⁺ 299.

Example 121 3-[(4-Bromo-2-fluorophenyl)amino]-N-ethoxyisonicotinamide

Step 1: Synthesis of 3-[(4-Bromo-2-fluoro)amino]isonicotinic acid.

3-Fluoro-isonicotinic acid (1 g, 7.09 mmol) and 4-bromo-2-fluoroaniline(1.35 g, 7.09 mmol) was added to 10 ml of dry THF and the mixture wascooled to −78° C. LiHMDS (1M in THF, 24.8 ml) was added and the mixturewas allowed to warm to room temperature over night. Solid ammoniumhydrochloride (2 g) was added and after 1 h the mixture was filtered andthe volatiles were removed in vacuo. The crude material was purified byflash-chromatography using C2-modified silica and a gradient of 0-12%methanol in DCM as eluent to give 1.21 g (3.89 mmol; 55% yield) of puredesired carboxylic acid product.

Step 2: 3-[(4-Bromo-2-fluoro)amino]isonicotinic acid from step 1 (300mg, 0.964 mmol) was dissolved in 6 ml dry DMF followed by the additionof DIPEA (1.16 mmol, 208 μl), PyBOP (1.16 mmol, 602 mg) andO-ethylhydroxylamine hydrochloride (1.93 mmol, 188 mg). The mixture wasstirred at ambient temperature over night and the volatiles were removedin vacuo. The crude material was purified by flash chromatography usingsilica gel and a gradient of 0-5% methanol in DCM as eluent to give 822mg of a mixture of the desired product and PyBop-derived phosphoramidebyproduct. A 215 mg sample thereof was further purified by preparativeRP-HPLC to give 23.3 mg (65.5 mmol) of the pure title compound. LC-MS(method III): rt=6.46 min; m/z [M+H]⁺ 354/356

Example 122 3-[(4-Iodo-2-fluorophenyl)amino]-N-ethoxyisonicotinamide

Step 1: Synthesis of 3-[(4-iodo-2-fluoro)amino]isonicotinic acid.

3-Fluoro-isonicotinic acid (1 g, 7.09 mmol) and 4-iodo-2-fluoroaniline(1.68 g, 7.09 mmol) was added to 10 ml of dry THF and the mixture wascooled to −78° C. LiHMDS (1M in THF, 24.8 ml) was added and the mixturewas allowed to warm to room temperature over night. Solid ammoniumhydrochloride (2 g) was added and after 1 h the mixture was filtered andthe volatiles were removed in vacuo. The crude material was purified byflash-chromatography using C2-modified silica and a gradient of 0-12%methanol in DCM as eluent to give 932 mg (2.32 mmol; 33% yield) of puredesired carboxylic acid product.

Step 2: 3-[(4-Iodo-2-fluoro)amino]isonicotinic acid from step 1 (200 mg,0.559 mmol) was dissolved in 4 ml dry DMF followed by the addition ofDIPEA (0.671 mmol, 121 μl), PyBOP (0.371 mmol, 350 mg) andO-ethylhydroxylamine hydrochloride (1.12 mmol, 110 mg). The mixture wasstirred at ambient temperature over night and the volatiles were removedin vacuo. The crude material was purified by preparative RP-HPLC to give113 mg (282 mmol; 50% yield) of the pure title compound. LC-MS (methodIII): rt=7.03 min; m/z [M+H]⁺ 402.

Example 123N-[3-(4-Iodo-2-methyl-phenylamino)-pyridine-4-carbonyl]-methanesulfonamide

3-[(4-Iodo-2-methylphenyl)amino]isonicotinic acid (example 3) (50 mg,0.141 mmol) was dissolved in 4 ml dry THF followed by the addition of1,1′-carbonyldiimidazole (CDI) (0.311 mmol, 50 mg), methanesulfonamide(0.169 mmol, 16.1 mg) and DBU (0.169 mmol, 26 mg). The mixture wasstirred for 16 h at 40° C. and the volatiles were removed in vacuo. Thecrude material was purified by preparative HPLC to give 20.3 mg (47μmol; 33% yield) of pure desired product. LC-MS (method III): rt=2.74min; m/z [M+H]⁺ 432.

Example 124N-((S)-2,3-Dihydroxy-propoxy)-3-(4-iodo-2-methyl-phenylamino)-isonicotinamide

The title compound was synthesized by the procedure as described forExample 119 usingO—((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine as abuilding block. LC-MS (method III): rt=3.22 min; m/z [M+H]+ 444.

Example 125 3-(4-Bromo-2-fluoro-phenylamino)-2-chloro-isonicotinic acid

2-Chloro-3-fluoro-isonicotinic acid (200 mg, 1.14 mmol) and4-bromo-2-fluoroaniline (217 mg, 1.14 mmol) were added to 5 ml of dryTHF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 4.0 ml) wasadded and the mixture was allowed to warm to room temperature overnight. Solid ammonium hydrochloride (1 g) was added and after 1 h themixture was filtered and the volatiles were removed in vacuo. The crudematerial was purified by flash-chromatography using a gradient of 0-12%methanol (containing 0.5% formic acid) in DCM as eluent to give 213 mg(0.617 mmol; 54% yield) of pure desired carboxylic acid product. LC-MS(method III): rt=4.42 min; m/z [M+H]+ 386/388.

Example 1265-[3-(4-Bromo-2-fluoro-phenylamino)-pyridin-4-yl]-3H-[1,3,4]oxadiazol-2-one

Step 1: Synthesis of 3-(4-Bromo-2-fluoro-phenylamino)-isonicotinic acidhydrazide.

3-(4-Bromo-2-fluoro-phenylamino)-isonicotinic acid (synthesis: seeexample 121 step 1) (1.5 g, 4.82 mmol) was dissolved in dry DMF (30 ml),N-t-butoxycarbonylhydrazide (1.27 g, 9.64 mmol), ByBOP (3.26 g, 6.27mmol) and DIPEA (2.52 ml, 14.5 mmol) were added and the mixture wasstirred at 60° C. for 14 h. The volatiles were evaporated, the residuewas redissolved in ethyl acetate and washed consecutively with saturatedNaHCO₃, water and brine and dried over sodium sulfate. The volatileswere evaporated and the crude material was purified byflash-chromatography using a gradient of 0-10% methanol in DCM aseluent. The Boc-protected hydrazide was treated with 4N HCl in dioxane(40 ml) at ambient temperature for 14 h and the volatiles were removedunder reduced pressure to give 1.59 g (4.66 mmol) of the crudehydrazide.

Step 2: The material derived from step 1 was dissolved in DMF, DIPEA(1.14 ml,

6.52 mmol) and 1,1′-carbonyldiimidazole (CDI, 945 mg, 5.83 mmol) wereadded and the mixture was stirred at room temperature for 14 h. Thevolatiles were evaporated and the crude material was purified byflash-chromatography using a gradient of 30-80% ethyl acetate incyclohexane to give 888 mg (2.53 mmol, 52% yield, 2 steps) of the titlecompound. LC-MS (method V): rt=3.27 min; m/z [M+H]+ 351/353.

Example 1272-{5-[3-(4-Bromo-2-fluoro-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-ylamino}-ethanol

Step 1:5-[3-(4-Bromo-2-fluoro-phenylamino)-pyridin-4-yl]-3H-[1,3,4]oxadiazol-2-one(example 19, 100 mg, 0.277 mmol) was dissolved in ethanol (4 ml),ethanolamine (85 mg, 1.38 mmol) was added and the mixture was stirredfor 20 min at 160° C. in a microwave oven. The volatiles were removed togive the crude compound, which was used in the next step.

Step 2: Dry dichloromethane (10 ml) was added to the product derivedfrom step 1, triphenylphosphine (113 mg, 0.429 mmol), triethylamine (58μl, 0.416 mmol) and carbon tetrachloride (107 μl, 1.11 mmol) were added.The mixture was heated at 100° C. for 10 min in a microwave oven, thevolatiles were removed and the crude material was purified bypreparative HPLC to give 43 mg (40% yield) of the title compound. LC-MS(method III): rt=4.92 min; m/z [M+H]+ 394/396.

Example 128N-{5-[3-(4-Bromo-2-fluoro-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-yl}-N′-methyl-ethane-1,2-diamine

Step 1:5-[3-(4-Bromo-2-fluoro-phenylamino)-pyridin-4-yl]-3H-[1,3,4]oxadiazol-2-one(example 19, 100 mg, 0.277 mmol) was dissolved in ethanol (3 ml),N-(2-aminoethyl)-N-methylcarbamic acid t-butylester (96 mg, 0.554 mmol)was added and the mixture was stirred for 20 min at 150° C. in amicrowave oven. The volatiles were removed to give the crude compound,which was used in the next step.

Step 2: Dry dichloromethane (5 ml) was added to the product derived fromstep 1 followed by triphenylphosphine (113 mg, 0.429 mmol),triethylamine (58 μl, 0.416 mmol) and carbon tetrachloride (107 μl, 1.11mmol). The mixture was heated at 1° C. for 20 min in a microwave oven,the volatiles were removed and the crude material was purified bypreparative HPLC to give 87 mg (62% yield) of the Boc-protected titlecompound. The material was treated with 4N HCl in dioxane (4 ml) for 1 hat ambient temperature and the volatiles were removed to give the puretitle compound. LC-MS (method V): rt=1.94 min; m/z [M+H]+ 407/409.

Example 129[4-(5-Allylamino-[1,3,4]oxadiazol-2-yl)-pyridin-3-yl]-(4-bromo-2-methyl-phenyl)-amine

Step 1: 3-(4-Bromo-2-methyl-phenylamino)-isonicotinic acid hydrazide wasprepared from 3-[(4-bromo-2-methylphenyl)amino]isonicotinic acid(example 2) by the procedure as described for example 126 step 1.

Step 2: 3-(4-Bromo-2-methyl-phenylamino)-isonicotinic acid hydrazide(0.426 mmol) was dissolved in 5 ml THF and treated with allylisocyanate(110 mg, 0.852 mmol) followed by DIPEA (110 mg, 0.852 mmol) and themixture was stirred for 2 h at ambient temperature. The volatiles wereremoved to give the crude compound, which was used for the next step.

Step 3: The product derived from step 2 was cyclized by the proceduredescribed for example 127 step 2. LC-MS (method III): rt=6.99 min; m/z[M+H]+ 386/388.

Assay 1: MEK-1 Enzyme Assay (LANCE-HTRF)

The activity of the compounds of the present invitation may bedetermined by the following procedure: Inhibition of human MEK1 kinaseactivity was monitored with a homogenous, fluorescence based assay. Theassay uses time resolved fluorescence resonance energy transfer to probefor phosphorylation of ERK1 by MEK1. The assay is carried out in lowvolume 96 well microtiterplates. In a total volume of 15 μl, compoundsare incubated with 100 nM MEK1, 15 μM ATP, 300 nM ERK2 employing abuffer containing 20 mM TRIS/HCl, 10 mM MgCl2 , 100 μM NaVO4, 1 mM DTT,and 0.005% Tween 20 (pH 7.4). After two hours, 5 nM Europium-anti-PY20(Perkin Elmer) and 50 nM Anti-GST-Allophycocyanin (CisBio) in buffercontaining 50 mM EDTA and 0.05% BSA are added and the reaction incubatedfor one hour in the dark. Time-resolved fluorescence is measured using aLJL-Analyst (Molecular Devices) with an excitation wavelength of 340 nmand an emission wavelength of 665 nm. The final concentration of DMSO is2%. To assess the inhibitory potential of the compounds, IC50-valueswere determined.

In this assay compounds of the invention exhibited IC50s within certainranges. The following compounds exemplify such activity with “+” meaning1 μM<IC50≦10 μM and “++” IC50≦1 μM. All results are shown in Table 1.

Assay 2: Tumor Cell Proliferation Assays (ATP Lite)

Murine colon C26, human melanoma A375 and MeI5 or human pancreaticMiaPaCa-2 cells were plated in 96 well Corning white plates (1500cells/well for C26, and 2000 cells/well for A375, and MiaPaCa-2) andcultured overnight at 37° C. in 5% CO2. Inhibitors were serially dilutedin 100% DMSO and subsequently added to cells to reach a finalconcentration of 0.25% DMSO. The cells were incubated for 4 days in thepresence of test compounds in cell growth media (DMEM with 10% fetalbovine serum, 2 mM glutamine for C26, and MiaPaCa-2, and RPMI with 10%fetal bovine serum, 2 mM glutamine for A375). Cell proliferation wasquantitated using the ATP lite cell proliferation kit (Packard).Inhibition of cell proliferation is shown in Table 1. Columns 4-6 showthe concentration of compounds required to induce 50% cell death (IC50in μM) of human end ometriotic cells. With “+” meaning 3 μM<IC50≦10 μMand “++” IC50≦3 μM and “n.d.” means not determined. Few compounds werealso tested on human melanoma cell MeI5. Compound of Example #124 showedan IC50 of “++”, the compound of Example 4 showed an IC50 of “+” and thecompound of Example 5 showed an IC50 of “++”.

Assay 3: Microsomal Stability Assay

Compounds were tested on their stability in human, rat and mouse livermicrosomal preparations (HLM, RLM and MLM respectively). At a finalconcentration of 3 μM, compounds were incubated at 37° C. with 0.5 mg/mlhuman, rat or mouse liver microsomes in a buffer containing 50 mMphosphate, pH 7.4 and 2 mM NADPH. Pooled human liver microsomes orpooled male rat liver microsomes (Sprague Dawley) were obtained fromNatuTec (Frankfurt, Germany). Incubations without NADPH served asnegative controls. Reactions were stopped after 0, 15, 30, 45 or 60 minby the addition of acetonitrile and microsomes were pelleted bycentrifugation (10 min at 6200×g). Supernatants were analyzed by HPLCregarding the concentration of mother compound Finally, the half life ofcompounds in the regarding microsomal preparation was calculated.Results are shown in Table 2 Wherein “+” means t_(1/2) of 1-30 min, “++”means t_(1/2) of 31-120 min and “+++” means t_(1/2) of >120 min.

Assay 4: Caco-2 Permeability Assay

Caco-2 cells obtained from the ATCC at passage number 27 are used. Cells(passage number 40-60) were seeded on to Millipore Multiscreen Caco-2plates or Falcon HTS inserts at 1×105 cells/cm2. Cells were cultured for20 days in DMEM and media was changed every two or three days. On day 20the permeability study was performed.

Permeability was studied by applying compound to the apical surface ofcell monolayers and measuring compound permeation into the basolateralcompartment. The experiment was also performed in the reverse direction(B-A) to investigate active transport. Hanks Balanced Salt Solution(HBSS) pH 7.4 buffer with 25 mM HEPES and 10 mM glucose at 37° C. wasused as the medium in permeability studies. Incubations were carried outin an atmosphere of 5% CO₂ with a relative humidity of 95%.

The monolayers were prepared by rinsing both basolateral and apicalsurfaces twice with HBSS at 37° C. Cells were then incubated with HBSSin both apical and basolateral compartments for 40 minutes to stabilizephysiological parameters.

HBSS was then removed from the apical compartment and replaced with testcompound dosing solutions. The solutions were made by diluting 10 mMDMSO concentrates with HBSS to give a final test compound concentrationof 10 μM (final DMSO concentration adjusted to 1%). The fluorescentintegrity marker lucifer yellow was also included in the dosingsolution. Analytical standards were made from dosing solutions. Testcompound permeability was assessed in duplicate. On each plate compoundsof known permeability characteristics were run as controls.

The apical compartment inserts were then placed into ‘companion’ platescontaining fresh HBSS. For basolateral to apical (B-A) experiments theexperiment was initiated by replacing buffer in the inserts then placingthem in companion plates containing dosing solutions. At 120 minutes thecompanion plate was removed and apical and basolateral samples dilutedfor analysis by LC-MS/MS (the donor compartment was also sampled topermit determination of starting concentration after non-specificbinding has occurred).

Analysis

The integrity of the monolayers throughout the experiment is checked bymonitoring lucifer yellow permeation using fluorimetric analysis.Lucifer yellow permeation was low if monolayers have not been damaged.Test and control compounds were quantified by LC-MS/MS cassette analysisusing a 5-point calibration with appropriate dilution of the samples.Should lucifer yellow Papps were above QC limits in more than one wellper test compound, the compound was re-tested.

The permeability coefficient for each compound (P_(app)) was calculatedfrom the following equation:P _(app) =[dQ/dt]/[C ₀ ×A]

Whereby dQ/dt is the rate of permeation of the drug across the cells, C₀is the donor compartment concentration at time zero and A is the area ofthe cell monolayer. C₀ is obtained from analysis of the donorcompartment at the end of the incubation period.

Test compounds were grouped into low, medium or high absorptionpotential based on comparison with control compounds, which have knownhuman absorption.

In addition, permeation was studied in both directions across the cells,and an asymmetry index was reported from mean A-B and B-A data. This wasderived from:P _(app(B-A)) /P _(app(A-B))

Results are shown in Table 2. Wherein “+” means a caco A-B and caco B-Avalue of 1-10 and “++” means a caco A-B and caco B-A value of 11-100.

TABLE 1 Results of MEK enzyme assay and tumor cell proliferation assayMEK IC50 [μM] IC50 [μM] IC50 [μM] Example # inhibition C26 A375 Miapaca1 ++ 2 ++ 3 ++ 4 ++ ++ n.d. 5 ++ + ++ n.d. 6 + 7 ++ ++ ++ ++ 8 ++ ++ ++++ 9 ++ + ++ n.d. 10 ++ + ++ ++ 11 ++ ++ ++ ++ 12 ++ ++ ++ ++ 13 ++ ++++ ++ 14 ++ ++ ++ ++ 15 ++ ++ ++ ++ 16 ++ ++ ++ ++ 17 ++ ++ ++ ++ 18 ++++ ++ ++ 19 ++ + ++ ++ 20 ++ ++ ++ ++ 21 ++ + ++ + 22 ++ ++ ++ ++ 23 ++++ ++ ++ 24 ++ ++ ++ ++ 25 ++ ++ ++ ++ 26 ++ + ++ + 27 ++ + + + 28 ++ +++ + 29 ++ + ++ + 30 ++ ++ ++ ++ 31 ++ ++ ++ ++ 32 ++ ++ ++ ++ 33 ++ ++++ ++ 34 ++ + ++ + 35 ++ ++ ++ ++ 36 ++ ++ ++ ++ 37 ++ n.d. n.d. n.d.38 + n.d. n.d. n.d. 39 ++ ++ ++ ++ 40 ++ + ++ + 41 ++ ++ ++ ++ 42 ++ +++ + 43 ++ + ++ + 44 ++ + ++ + 45 ++ + ++ + 46 ++ + ++ + 47 ++ ++ ++ ++48 ++ ++ ++ ++ 49 ++ ++ ++ ++ 50 ++ + ++ + 51 ++ + ++ ++ 52 + n.d. n.d.n.d. 53 ++ ++ ++ ++ 54 + + 55 ++ + ++ + 56 + + ++ + 57 + n.d. n.d. n.d.58 ++ ++ ++ ++ 59 + n.d. n.d. n.d. 60 ++ ++ ++ ++ 61 ++ + 62 ++ + ++ 63++ ++ 64 ++ + ++ + 65 ++ + ++ + 66 ++ ++ 67 ++ ++ ++ ++ 68 ++ ++ ++ ++69 ++ + ++ 70 ++ ++ ++ ++ 71 ++ + ++ + 72 ++ + ++ + 73 ++ 74 ++ + ++ +75 ++ ++ ++ ++ 76 ++ + ++ + 77 ++ + ++ + 78 ++ + ++ 79 ++ ++ ++ ++ 80 ++++ + 81 ++ + ++ + 82 ++ + ++ + 83 ++ ++ ++ ++ 84 ++ + ++ 85 ++ + ++ + 86++ + ++ + 87 ++ ++ + 88 ++ + + + 89 + n.d. n.d. n.d. 90 ++ ++ ++ ++ 91++ + ++ + 92 ++ + ++ + 93 ++ + ++ + 94 ++ + 95 ++ 96 ++ ++ ++ ++ 97 ++++ ++ ++ 98 ++ + ++ + 99 ++ + ++ + 100 ++ + ++ + 101 ++ + ++ + 102 ++ +++ + 103 ++ n.d. nd. n.d. 104 ++ n.d. n.d. nd. 105 ++ n.d. n.d. n.d. 106++ n.d. n.d. n.d. 107 ++ n.d. n.d. n.d. 108 ++ n.d. n.d. n.d. 109 ++n.d. n.d. n.d. 110 ++ n.d. n.d. n.d. 111 ++ n.d. nd. n.d. 112 ++ n.d.n.d. n.d. 113 ++ n.d. nd. n.d. 114 ++ n.d. n.d. nd. 115 ++ n.d. n.d.n.d. 116 ++ n.d. n.d. n.d. 117 n.d. n.d. n.d. n.d. 118 + n.d. n.d. n.d.119 + n.d. n.d. n.d. 120 n.d. n.d. n.d. 121 ++ n.d. n.d. n.d. 122 n.d.n.d. n.d. 123 ++ n.d. n.d. n.d. 124 ++ + n.d. n.d. 125 ++ n.d. n.d. n.d.126 + n.d. n.d. n.d. 127 n.d. n.d. n.d. 128 ++ n.d. n.d. n.d. 129 ++ nd.n.d. n.d.

TABLE 2 Results of caco-2 permeability assay and microsomal stabilityassay HLM t_(1/2) RLM t_(1/2) MLM t_(1/2) Example # [min] [min] [min]Caco A-B Caco B-A 4 ++ ++ n.d. n.d. n.d. 9 +++ +++ +++ + ++ 123 ++ +n.d. n.d. n.d. 127 +++ +++ + ++ ++ 128 +++ ++ n.d. ++ ++ 129 +++ ++ +++++ ++

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: R₁, R₂, R₉, R₁₀,R₁₁ R₁₂, R₁₃ and R₁₄ are independently selected from: hydrogen, halogen,cyano, nitro, azido, —OR₃, —NR₄C(O)OR₆, —OC(O)R₃, —NR₄S(O)_(j)R₆,—S(O)_(j)NR₃R₄, —S(O)_(j)NR₄C(O)R₃, —C(O)NR₄S(O)_(j)R₆, —S(O)_(j)R₆,—NR₄C(O)R₃, —C(O)NR₃R₄, —NR₅C(O)NR₃R₄, —NR₅C(NCN)NR₃R₄, NR₃R₄, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR₄R₅)_(m)-aryl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —O(CR₄R₅)_(m)-aryl, —NR₄(CR₄R₅)_(m)-aryl,—O(CR₄R₅)_(m)-heteroaryl, —NR₄(CR₄R₅)_(m), heteroaryl,—O(CR₄R₅)_(m)-heterocyclyl, —NR₄(CR₄R₅)_(m)-heterocyclyl and —S(C₁-C₂alkyl) substituted with 1 to 5 fluorines, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is independentlysubstituted or unsubstituted; R₃ is selected from: hydrogen,trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and aryl; wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl and heterocyclyl isindependently substituted or unsubstituted; and wherein aryl isoptionally substituted with 1 to 5 groups independently selected from:oxo, halogen, nitro, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, OCH₂F, azido,NR′SO₂R″″, SO₂NR″, C(O)R′, C(O)OR′, OC(O)R′, NR′C(O)OR″″, NR′C(O)R″,C(O)NR′R″, SR″″, S(O)R″″, SO₂R′, NR′R″, NR′C(O)NR″R′″, NR′C(NCN)NR″R′″,OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R₄ is selected from hydrogen or C₁-C₆ alkyl, whereinalkyl may be substituted or unsubstituted; or R₃ and R₄ can be takentogether with the atom to which they are attached to form a 4 to 10membered heteroaryl or heterocyclic ring, each of which is substitutedor unsubstituted; R₅ is hydrogen or C₁-C₆ alkyl, wherein alkyl may besubstituted or unsubstituted; or R₄ and R₅ can be taken together withthe atom to which they are attached to form a 4 to 10 memberedcarbocyclic, heteroaryl or heterocyclic ring, each of which issubstituted or unsubstituted; R₆ is selected from: trifluoromethyl,C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein eachalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is independentlysubstituted or unsubstituted; R′, R″ and R′″ are independently selectedfrom: hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, aryl and arylalkyl; R″″ isselected from: C₁-C₄ alkyl, C₁-C₄ alkenyl, aryl and arylalkyl; W is—C(O)OR₁₅, —C(O)NR₄R₁₅, —C(O)NR₄OR₁₅, —C(O)NR₄S(O)_(j)R₆,—C(O)NR₄NR₄R₁₅, —NR′C(O)R′, —NR′S(O)_(j)R′, —NRC(O)NR′R″,NR′S(O)_(j)NR′R″, or —C(O)NR₄NR₄C(O)R₁₅; provided that W is not —C(O)OH;R₁₅ is selected from: hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl and heterocyclyl is independently substituted orunsubstituted; R₁₆ is selected from hydrogen or C₁-C₁₀ alkyl; or R₁₅ andR₁₆ taken together with the atom to which they are attached form a 4 to10 membered cyclic ring with 1 or 2 nitrogen atoms and optionally anoxygen atom, said ring being substituted or unsubstituted; X is N orN⁺O⁻; m is 0, 1, 2, 3, 4 or 5; and j is 1 or 2; with the proviso that3-phenylamino-isonicotinic acid methyl ester, and3-oxo-3-(3-phenylamino-pyridin-4-yl)-propionic acid ethyl ester are notincluded.
 2. A compound according to claim 1 of formula (II):

or a pharmaceutically acceptable salt, solvate or prodrug thereof,wherein: R₁, R₂, R₉, R₁₀, R₁₁ R₁₂, R₁₃ and R₁₄ are independentlyselected from: hydrogen, halogen, cyano, nitro, azido, —OR₃,—NR₄C(O)OR₆, —OC(O)R₃, —NR₄S(O)_(j)R₆, —S(O)_(j)NR₃R₄,—S(O)_(j)NR₄C(O)R₃, —C(O)NR₄S(O)_(j)R₆, —S(O)_(j)R₆, —NR₄C(O)R₃,—C(O)NR₃R₄, —NR₅C(O)NR₃R₄, —NR₅C(NCN)NR₃R₄, —NR₃R₄, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR₄R₅)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR₄R₅)_(m)-aryl, —NR₄(CR₄R₅)_(m)-aryl, —O(CR₄R₅)_(m)-heteroaryl,—NR₄(CR₄R₅)_(m), heteroaryl, —O(CR₄R₅)_(m)-heterocyclyl,—NR₄(CR₄R₅)_(m)-heterocyclyl and —S(C₁-C₂ alkyl) substituted with 1 to 5fluorines; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl is independently substituted orunsubstituted; R₃ is selected from: hydrogen, trifluoromethyl, C₁-C₁₀alkyl, C₂₋₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,aryl and heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl and heterocyclyl is independently substituted orunsubstituted; and wherein aryl is optionally substituted with 1 to 5groups independently selected from: oxo, halogen, nitro, CF₃, CHF₂,CH₂F, OCF₃, OCHF₂, OCH₂F, azido, NR′SO₂R″″, SO₂NR″, C(O)R′, C(O)OR′,OC(O)R′, NR′C(O)OR″″, NR′C(O)R″, C(O)NR′R″, SR″″, S(O)R″″, SO₂R′, NR′R″,NR′C(O)NR″R′″, NR′C(NCN)NR″R′″, OR′, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 is selectedfrom hydrogen or C₁-C₆ alkyl, wherein alkyl may be substituted orunsubstituted; or R₃ and R₄ can be taken together with the atom to whichthey are attached to form a 4 to 10 membered heteroaryl or heterocyclicring, each of which is substituted or unsubstituted; R₅ is selected fromhydrogen or C₁-C₆ alkyl, wherein alkyl may be substituted orunsubstituted; or R₄ and R₅ can be taken together with the atom to whichthey are attached to form a 4 to 10 membered carbocyclic, heteroaryl orheterocyclic ring, each of which is substituted or unsubstituted; R₆ isselected from trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; wherein each alkyl, cycloalkyl, aryl, heteroaryl andheterocyclyl is independently substituted or unsubstituted; R′, R″ andR′″ are independently selected from: hydrogen, C₁-C₄ alkyl, C₂-C₄alkenyl, aryl and arylalkyl; R″″ is selected from: C₁-C₄ alkyl, C₁-C₄alkenyl, aryl and arylalkyl; W is —C(O)OR₁₅, —C(O)NR₄R₁₅, —C(O)NR₄OR₁₅,or —C(O)NR₄S(O)_(j)R₆; provided that W is not C(O)OH; R₁₅ is selectedfrom: hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl is substituted or unsubstituted; R₁₆ is selected fromhydrogen or C₁-C₁₀ alkyl; or R₁₅ and R₁₆ taken together with thenitrogen atom to which they are both attached form a 4 to 10 memberedcyclic ring with 1 or 2 nitrogen atoms and optionally an oxygen atom,said ring being substituted or unsubstituted; X is N or N⁺O⁻; m is 0, 1,2, 3, 4 or 5; and j is 1 or
 2. 3. A compound according to claim 1,wherein: R₁, R₂, R₉, R₁₁ are independently selected from: hydrogen,halo, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,cyano, nitro, —OR₃ and —NR₃R₄; wherein each alkyl, alkenyl, alkynyl,cycloalkyl is independently and optionally substituted with one to fivehalogens; R₁₀ and R₁₂ are selected independently from: hydrogen, halo,C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cyano,nitro, azido, —NR₄SO₂R₆, —SO₂NR₃R₄, —SO₂R₆, —C(O)NR₃R₄,—S(O)_(j)NR₄C(O)R₃, —C(O)NR₄S(O)_(j)R₆, —OR₃, —NR₃R₄ and —S(C₁-C₂ alkyl)substituted with 1 to 5 fluorines; wherein each alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl and heterocyclyl is independentlysubstituted or unsubstituted; R₁₃ and R₁₄ are independently selectedfrom: H, F, Cl, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₂-C₄ alkenyl, and C₂-C₄alkynyl; wherein each alkyl, alkenyl, cycloalkyl, and alkynyl isindependently and optionally substituted with one to five halogens; W is—C(O)OR₁₅, —C(O)NR₄R₁₅, —C(O)NR₄OR₁₅,—C(O)(C₂-C₁₀ alkyl), or—C(O)NR₄S(O)_(j)R₆; R₁₅ is selected from: hydrogen, C₁-C₄ alkyl, C₁-C₄alkenyl, and C₄-C₆ cycloalkylalkyl; wherein each alkyl or alkenyl isindependently and optionally substituted by 1 or 2 OH, C₁-C₄ alkoxy orNR′R″; R₁₆ is hydrogen or C₁-C₄ alkyl; and R′ and R″ are eachindependently selected from: hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, aryland arylalkyl.
 4. A compound according to claim 1 wherein: R₁ isselected from H and F; R₂ is selected from: hydrogen, F, Cl, and Me;wherein the methyl group is optionally substituted with one to threefluorines; R₉ is selected from: H, F, and Cl; R₁₀ is selected from: H,F, Cl, Br, nitro, —SO₂NR₃R₄ or —C(O)NR₃R₄, -Me, and —OMe, wherein themethyl groups are optionally substituted with one to three fluorines;R₁₁ is selected from: H, F, Cl, Br, Me, and —OMe; wherein the methylgroups are optionally substituted with one to three fluorines; R₁₂ isselected from: H, F, Cl, Br, nitro, Me, —SCF₃, —SCHF₂, —SCH₂F,—SO₂NR₃R₄, —C(O)NR₃R₄ and —OMe; wherein the methyl groups are optionallysubstituted with one to three fluorines; R₃ and R₄ are C₁-C₆ alkyl,independently and optionally substituted by 1 or 2 alkyl amino or alkoxygroups; or R₃ and R₄ taken together with the nitrogen atom to which theyare attached form a cyclic ring with 1 or 2 nitrogen atoms andoptionally an oxygen atom, said ring being optionally substituted by 1or 2 alkyl amino or alkoxy groups; R₁₃ is H or F; R₁₄ is H or F; W is—C(O)NR₄OR₁₅; R₁₅ is C₁-C₄ alkyl or C₁-C₄ alkenyl; wherein each isindependently and optionally substituted with 1 to 3 —OH, —OMe, —NH₂,—N(methyl)₂ or —N(ethyl)₂; R₁₆ is hydrogen or C₁-C₄ alkyl; or R₁₆ andR₁₅ taken together with the nitrogen atom to which they are attachedform a 4 to 10 membered cyclic ring with 1 or 2 nitrogen atoms andoptionally an oxygen atom, said ring being optionally substituted by 1or 2 alkyl amino, amino, hydroxy or alkoxy groups; and Y is O, S or NR′.5. A compound according claim 1 wherein: W is —C(O)NR₄OR₁₅; R₄ ishydrogen; R₁₅ is selected from: C₁-C₄ alkyl and C₁-C₄ alkenyl; whereineach is independently and optionally substituted by 1 or 2 —OH, C₁-C₄alkoxy or —NR′R″; R′ and R″ are independently hydrogen, methyl or ethyl;and Y is O.
 6. A compound according to claim 1, wherein the compound isselected from the group consisting of:N-(2,3-Dihydroxy-propoxy)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide;3-[(2-chloro-4-iodophenyl)amino]-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}isonicotinamide;N-(2,3-Dihydroxy-propoxy)-3-(4-iodo-2-methyl-phenylamino)-isonicotinamide;3-(2-Chloro-4-iodo-phenylamino)-isonicotinic acid methyl ester;3-(2-Chloro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-propyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide;[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-morpholin-4-yl-methanone;N-Ethyl-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-piperidin-1-yl-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(3-imidazol-1-yl-propyl)-isonicotinamide;N-Benzyl-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Chloro-4-iodo-phenylamino)-N-methyl-isonicotinamide;3-(2-Chloro-4-iodo-phenylamino)-N,N-dimethyl-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-methoxy-ethyl)-N-methyl-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-morpholin-4-yl-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-phenoxy-ethyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-[2-(2-methoxy-phenyl)-ethyl]-isonicotinamide;N-[2-(3-Chloro-phenyl)-ethyl]-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-isonicotinamide;2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid N′-phenyl-hydrazide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-piperidin-1-yl-ethyl)-isonicotinamide;{1-[3-(2-Fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-piperidin-4-yl}-carbamicacid tert-butyl ester;3-(2-Fluoro-4-iodo-phenylamino)-N-(3-morpholin-4-yl-propyl)-isonicotinamide;3-(2-Chloro-4-iodo-phenylamino)-N-(5-hydroxy-pentyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-N-methyl-isonicotinamide;2-Chloro-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(4-hydroxy-butyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-pyridin-2-ylmethyl-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-propyl)-isonicotinamide;N-Azepan-1-yl-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;2-Chloro-N-(2,3-dihydroxy-propoxy)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;(4-Amino-piperidin-1-yl)-[3-(2-fluoro-4-iodo-phenylamino)-pyridin-4-yl]-methanone;N′-[3-(2-Fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-hydrazinecarboxylicacid tert-butyl ester;4-({[3-(2-Fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-amino}-methyl)-benzoicacid; N-Cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-propyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acidN′-pyridin-2-yl-hydrazide; 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinicacid N′-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazide;3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide;N-Cyclopropylmethyl-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Chloro-4-ethynyl-phenylamino)-N-(2,3-dihydroxy-propoxy)-isonicotinamide;3-Methoxy-benzoic acidN′-[3-(2-fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-hydrazide;3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acidN′-(7-chloro-quinolin-4-yl) -hydrazide;2-(4-Dimethylamino-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinicacid; N-Cyclobutyl-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-indan-1-yl-isonicotinamide;N-Cyclopentyl-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;N-Cyclohexyl-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;N-(1,2-Dimethyl-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;N-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;N-(2-Acetylamino-ethyl)-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide;N-tert-Butoxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-isonicotinamide;3-(4-Iodo-phenylamino)-isonicotinamide;2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;2-Bromo-N-([1,3]dioxolan-4-ylmethoxy)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-hydroxy-propyl)-isonicotinamide;2-Bromo-N-(2,3-dihydroxy-propoxy)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-imidazol-1-yl-propyl)-isonicotinamide;2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide;N-(2,3-Dihydroxy-propoxy)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-isonicotinamide;N-Allyloxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide;3-(2-Chloro-4-iodo-phenylamino)-N-isobutoxy-isonicotinamide;N-(3-Chloro-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Chloro-4-iodo-phenylamino)-N-methoxy-isonicotinamide;N-Benzyloxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide;N-Bicyclo[2.2.1]hept-2-yl-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyphenoxypropyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(tetrahydro-pyran-2-yloxy)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-p-tolyl-ethyl)-isonicotinamide;N-{1-[3-(2-Fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-piperidin-4-yl}-2-p-tolyl-acetamide;2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-methoxy-ethyl)-isonicotinamide;2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamide;N-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-(2-fluoro-4-iodo-phenylamino)-1-oxy-isonicotinamide; 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acidN′-m-tolyl-hydrazide;N-Benzyloxy-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;{[3-(2-Fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-aminooxy}-aceticacid;N-(2,4-Difluoro-benzyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(3-iodo-benzyl)-isonicotinamide;N-(2,3-Dihydroxy-propoxy)-3-(4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-1-oxy-isonicotinamide;N-(2,2-Diethoxy-ethyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid N′-p-tolyl-hydrazide;3-(2-Fluoro-4-iodo-phenylamino)-2-methyl-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acidN′-(3,5-bis-trifluoromethyl-phenyl) -hydrazide;4-(2-{[3-(2-Fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-amino}-ethyl)-benzoicacid;3-(2-Fluoro-4-iodo-phenylamino)-N-pentafluorophenylmethoxy-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(3-methoxy-phenyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(3-fluoro-5-trifluoromethyl-benzyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(3-hydroxy-benzyl)-isonicotinamide;N-(4,4-Diethoxy-butyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;N-(4-Fluoro-benzyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2,2,2-trifluoro-ethyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(1-hydroxymethyl-cyclopentyl)-isonicotinamide;N-(1-Carbamoyl-2-hydroxy-ethyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-cyclohexyl)-isonicotinamide;N-(1,1-Bis-hydroxymethyl-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;N-(2,3-Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(3-piperazin-1-yl-propyl)-isonicotinamide;3-(2-Fluoro-4-iodo-phenylamino)-N-(3-fluoro-5-trifluoromethyl-benzyl)-iso-nicotinamide;3-[(4-Bromo-2-fluorophenyl)amino]-N-ethoxyisonicotinamide;3-[(4-Iodo-2-fluorophenyl)amino]-N-ethoxyisonicotinamide;N-[3-(4-Iodo-2-methyl-phenylamino)-pyridine-4-carbonyl]-methanesulfonamide;N—((S)-2,3-Dihydroxy-propoxy)-3-(4-iodo-2-methyl-phenylamino)-isonicotinamide;or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a MEK inhibitor according to claim 1 and apharmaceutically acceptable excipient.
 8. A process for the manufactureof compounds according to Formula (I):

said process comprising the step of reacting the following startingmaterial:

with an amine of formula R₁—X—NHR₂ in the presence of a coupling agent,and thereby forming a compound according to Formula I; wherein X is C, Nor O; Y is N or N⁺O⁻; Q and R are independently selected from: hydrogen,halogen, cyano, nitro, azido, —OR₃, —C(O)R₃, —C(O)OR₃, —NR₄C(O)OR₆,—OC(O)R₃, —NR₄S(O)_(j)R₆, —S(O)_(j)NR₃R₄, —S(O)_(j)NR₄C(O)R₃,—C(O)NR₄S(O)_(j)R₆, S(O)_(j)R₆, —NR₄C(O)R₃, —C(O)NR₃R₄, —NR₅C(O)NR₃R₄,—NR₅C(NCN)NR₃R₄,—NR₃R₄, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR₄R₅)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, —O(CR₄R₅)_(m)-aryl,—NR₄(CR₄R₅)_(m)-aryl, —O(CR₄R₅)_(m)-heteroaryl, —NR₄(CR₄R₅)_(m),heteroaryl, —O(CR₄R₅)_(m)-heterocyclyl, —NR₄(CR₄R₅)_(m)-heterocyclyl and—S(C₁-C₂ alkyl) substituted with 1 to 5 fluorines; R¹ is selected from:—C(O)R¹⁵, R¹⁵, hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, aryl and arylalkyl;R² is selected from: H, C₁-C₆ alkyl, C₂-C₄ alkenyl, aryl, and arylalkyl;and R₁₅ is selected from: hydrogen, —CF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl.
 9. The process of claim 8, wherein the coupling agentis Benzotriazole-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate(PyBOP), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC) or Dicyclohexylcarbodiimide (DCC).